Download Candiolo Cancer Institute Fondazione del Piemonte per l

Candiolo Cancer Institute
Fondazione del Piemonte per l’Oncologia
Istituto di Ricovero e Cura a Carattere Scientifico
Scientific Report 2014
www.ircc.it
Scientific Report 2014
Contents
About Us 5
Mission 7
Research Synopsis 9
Mechanisms of Cancer Onset and Progression
11
From Molecular Biology to “Precision Medicine”
29
Investigational Clinical Oncology51
Applied Clinical Research59
Clinical Services80
Educational Activities82
Core Facilities84
Grant Office and Research Administration
86
Electronic Data Processing86
List of Publications87
|3
THE CANDIOLO CANCER INSTITUTE
The Candiolo Cancer Institute is a private non-profit institution founded and supported by the Fondazione Piemontese per
la Ricerca sul Cancro-Onlus (FPRC) and operated by the Fondazione del Piemonte per l’Oncologia (FPO: a joint venture
between the FPRC and the Regione Piemonte). It is linked to the University of Torino Medical School. Its mission is a
significant contribution to fight cancer, by understanding the basics, and by providing state-of-the-art diagnostic and
therapeutic services. At the core of the Institute is the interface between molecular biology and medicine. The FPRC
provides enduring fund raising to complete and develop the Institute’s buildings and technologies to foster research.
From the left Paolo M Comoglio, Scientific Director of the Institute, Marco Boglione, President of the Fondazione del
Piemonte per l’Oncologia (FPO)-IRCCS, Giampiero Gabotto, Managing Director of FPO, Margaret Foti, Chief Executive
Officer of the American Association for Cancer Research (AACR) visiting the Institute, and Allegra Agnelli, President of
the Fondazione Piemontese per la Ricerca sul Cancro Onlus (FPRC).
25 November 2014
4 | About Us
CANDIOLO CANCER INSTITUTE
About Us | 5
MISSION
The Candiolo Cancer Institute is a biomedical and clinical research center entirely devoted to the study and the
treatment of cancer. Its mission is to transfer experimental preclinical information into clinical practice, through
the continuous flow of knowledge from the fields of genetics, molecular and cell biology and pathology.
The Institute aims to offer a significant contribution to the defeat of the disease through scientific research
and clinical practice of excellence. In order to fulfill these goals, the Institute: (i) capitalizes on knowledge by
conducting scientific research in oncology and – at the same time – promoting fast transfer of knowledge to
the clinical practice; (ii) provides assistance in cancer prevention, including the identification of genetic risk
factors; (iii) performs diagnostic studies, using state-of-the-art instrumentation and technology; (iv) provides a
full cycle of treatment on the premises, employing -besides the best conventional therapies– protocols for novel
targeted therapies and clinical trials for ‘precision medicine’.
Focus
Basic and clinical research make the Institute of Candiolo a center of excellence focussed on the study,
prevention and treatment of the dreadful complication of cancer, metastasis.
Basic Research
The current knowledge about the mechanisms of cancer onset and progression is provided by basic disciplines,
such as genetics, cell and developmental biology. Thanks to these studies, it is possible to classify tumors
not only on the basis of their site of origin and histopathological features, but , notably, by the identification
of the genetic lesion(s) that support their growth. The tasks of the Institute is basic research are aimed at
understanding the mechanisms that control normal cell functions responsible for proliferation, and at analyzing
how these mechanisms are corrupted during neoplastic transformation. The topics include signal transduction,
DNA duplication, cell division, differentiation, senescence, apoptosis and cell motility. Recent studies suggest
that anti-neoplastic therapy is really effective not only when it hits the appropriate molecular target (vide infra),
but especially when it hits the cells feeding the tumor mass. Indeed, most of the cells of the neoplastic
mass are quite innocuous and can be attacked with classical therapies, while only a small fraction of them
are resistant to treatment and able to regenerate the tumor. This small subpopulation includes the “cancer
stem cells” – strictly related to normal “stem cells” – which control the development of our organism during
embryonic life and allow us to renew worn parts in adult life. The up-to-date conceptualization of Cancer defines
it as a “somatic, genetic disease of the stem cells”.
2014 International Conference on Molecular Clinical Oncology ‘Precision Medicine’
From right to left, from the bottom to the top: Livio Trusolino, Paolo Comoglio, Manuel
Hidalgo, Giorgio Scagliotti, Salvatore Siena, Alberto Bardelli, Silvia Marsoni, Carla
Boccaccio, Maria Flavia Di Renzo, Gerard Evans, Filippo Montemurro, Federica
Di Nicolantonio, Guido Serini, Enrico Giraudo, James Brenton, Pietro Gabriele.
Top left: Antonino Sottile
6 | Mission
Translational Research (ECMO: Experimental Clinical Molecular Oncology)
Translational research is the “heart” of the Institute, bridging the gap between basic and clinical research. Based
on recent technological advances, genomic analysis makes possible –in a significant percentage of cases– the
identification of genetic alteration(s) with a “driver” role in tumor development. However, the contribution of
each lesion to the transformed phenotype remains elusive. Moreover, knowledge is still insufficient about the
mechanisms that control the lack of response to targeted therapies, even in the presence of the molecular
target (primary resistance), as well as on the mechanisms that lead to progressive attenuation of the response
after prolonged treatment (acquired resistance).
Mission| 7
RESEARCH SYNOPSIS
ECMO research aims at the fulfillment of some ambitious Goals to integrate the traditional prognostic and
diagnostic factors with a detailed characterization of the genetic and functional alterations of the tumor; to
identify new malfunctioning regulatory pathways in cancer; to isolate and study cancer stem cells; to develop
new preclinical platforms that can reliably disclose –and understand in detail– the prospective results of
clinical practice. The generation of this kind of knowledge is necessary to design clinical trials that will no
longer be based on empirical observations but on a strong rationale.
Investigational Clinical Oncology (INCO)
Cancer is a complex disease, tied to genetic lesions, that increase in number over time, as a consequence of
genetic instability and exposure to environmental carcinogens. Thus, a cell clone proliferates and invades
the adjacent tissues in an uncontrolled way. Since cancer cells contain several genetic anomalies, and tend
to accumulate more anomalies as time passes, cancer is a heterogeneous and hard-to-attack disease, just
because it would be necessary to aim at many targets that continuously change. The molecular lesions that
cause and sustain most tumors are, however, finite in number (the bona fide oncogenes). These findings
have drived clinical pharmacology to commit to an epochal effort to create drugs, called “targeted”, able to
contrast the function of specific oncogenes. The strategy of the Institute at Candiolo intends to make significant
contributions to the field of cancer targeted therapy by: (i) identifying pathologies and recruiting patients
sensitive to the therapies currently in use; (ii) planning and performing –in international networks – the related
clinical trials; (iii) developing translational and preclinical research aimed at designing new targeted therapies.
Molecular diagnosis and “precision” medicine
The success of targeted therapies is based on the rationale that the target molecule is ‘druggable’ –as a
consequence of the genetic anomaly– in the tumor but not in healthy tissue, and therefore its deactivation
has consequences restricted to the neoplastic mass, with a minimum of ‘off-target’ consequences, leading to
generic organ damage. This notion has two important clinical outcomes: first of all, before treating patients with
a given targeted therapy, it is necessary to verify the presence of the genetic lesion “predictive” of sensitivity to
the drug. Second –in the perspective of targeted therapies– tumors will be classified not only according to their
site of origin and/or morphological features, but also by the molecular lesion(s) which earmark them and, at
the same time, make them vulnerable to a targeted treatment. Therefore, new therapies are not only “targeted”
but also “personalized”. This new approach is called “precision medicine”.
Topic 1: The mechanisms of onset and progression of cancer
1.1 Role of Semaphorins in invasion, metastasis and angiogenesis
1.2 The plasma membrane in cell migration and invasiveness
1.3 Tumor angiogenesis
Topic 2: From Molecular Biology to ‘Precision Medicine’
2.1 Oncogenes and growth factors
2.2 Genetics of the response to anti-cancer therapy
2.3 Preclinical models of ‘personalized’ therapies
2.4 Resistance to targeted therapy
Topic 3: Investigative clinical research: rationale for the planning of clinical trials
3.1 HERACLES and ARES: ‘Precision medicine’ trials for metastatic colon carcinoma
3.2 HERLAP: ‘Personalized’ treatment of mammary carcinoma
3.3 AGNOSTOS: Therapy of metastatic cancers of unknown primary origin
Topic 4: Applied clinical research
4.1 Colorectal cancer: onset and progression
4.2 Implementation of current therapeutic strategies
4.3 Novel approaches to surgical oncology
4.4 Radiotherapy, imaging and laboratory medicine
Clinical Research
At the Institute, oncologists, surgeons and radiotherapists cooperate with scientists to design clinical trials based
on molecular data, intended to verify hypotheses and generate novel ones. In order to make this cooperation
productive, the Institute manages a daily net of interactions involving formal aspects (seminars and meetings),
training (refresher courses and lessons), operational efforts (contacts with pharmaceutical companies, and
management of regulatory instruments). Clinical Research is the last and more direct haven to improve the
assistance to cancer patients, providing them with the most appropriate, novel, safe and effective therapeutic
approach, according to the genetic characteristic of their own tumor , as an ultimate means of increasing their
life expectancy.
Paolo M.Comoglio MD
(Scientific Director)
8 | Mission
Research Synopsis | 9
Research Topic 1:
Mechanisms of cancer onset and progression.
The current knowledge on mechanisms of cancer onset and progression has been provided by basic disciplines,
such as cell biology, developmental biology and genetics. The tasks of Research Topic 1 are aimed at
understanding the mechanisms controlling the normal cell functions responsible for the regulation of cell
proliferation and at analyzing how these mechanisms are corrupted during neoplastic transformation. The
topics include signal transduction, DNA duplication and cell division processes, differentiation, senescence,
apoptosis and cell invasion. Special attention is given to the microenvironment and to the relations of the
neoplastic cell with adjacent cells. In the past, the angiogenic process and the vascularization of the tumor
mass have been studied in detail.
Research Topic 1 is focussed on:
1.1
The role of Semaphorins in invasiveness, metastases and angiogenesis
1.2
The plasma membrane in metastasis dissemination
1.3
Tumor angiogenesis
Ab Control
DN30Fab
Confocal microscopy pictures of H1993 cells. This is a lung cancer cell line that carries amplification of the MET
oncogene. Cells were stained with antibodies to reveal MET (shown in green in the merged images) and EEA1,
a marker of the early endosomal compartment (in red in the merged images). Nuclei are in blue. Pictures were
kept with identical settings. Left: the receptor accumulates at the plasma membrane in control cells. Right:
treatment with the anti-MET therapeutic antibody (DN30Fab) abrogates MET accumulation at the cell surface.
Bar is 10 μm.
10 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 11
Semaphorins: structure & functions
Luca Tamagnone MD
Laboratory of Cancer Cell Biology
Associate Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933204
Fax. +39.011.9933225
The elucidation of the functional role and molecular mechanisms by which Semaphorin genes control the
invasiveness of tumor cells and the formation of metastases will prompt the development of innovative diagnostic
and therapeutic approaches
Team
Michael Rehman, Sabrina Rizzolio, Lorena Capparuccia, Chiara Battistini, Gabriella Cagnoni,
Gurrapu Sreeharsha, Massimo Accardo
Biographical Sketch:
Semaphorins and Semaphorin Receptors in Cancer Progression.
Luca Tamagnone, MD, PhD started his research activity with Paolo Comoglio. During his training in the lab of
Kari Alitalo, he discovered new genes encoding tyrosine kinases, such as RYK and BMX (published in Oncoge-
Background:
ne, 1993 and 1994). On returning to Italy, Dr Tamagnone started working on a new family of receptors, the
Semaphorins and their receptors (Neuropilins and Plexins), beyond their role in embryo development and
Plexins (described in PNAS-USA, 1996). Three years later he published the identification of plexin ligands, the
morphogenesis, are relevant players in cancer progression and emerging targets for innovative therapeutic ap-
Semaphorins (in Cell, 1999). As tenured Associate Professor at the University of Torino, and Young Investigator
proaches. Semaphorins form a conserved family of over 20 members in vertebrates, which include transmem-
of the European Molecular Biology Organization, in 2001, Dr Tamagnone started his own lab in the Institute for
brane molecules (thought to elicit bi-directional signaling upon cell-cell contact) and secreted members. Se-
Cancer Research of Candiolo-Torino (IRCC). He focused his attention on semaphorin/plexin activities in cancer
creted semaphorins often act to restrict cell migration; for instance, they can negatively regulate angiogenesis,
cells, identifying fundamental signaling mechanisms and functional properties in the regulation of tumor pro-
preventing its pathological role in cancer. Certain semaphorins can play diverse functional roles in different cell
gression (e.g. Neuron, 2001; Nat Cell Biol, 2002; Nature, 2003; FASEB J, 2004; J Cell Sci, 2005). By exploiting
populations, due to the involvement of distinctive receptor complexes and signaling cascades. In particular, our
experimental models in vivo, he found that semaphorin signals regulate multiple steps of tumor progression:
lab demonstrated that Sema3A and Sema3E are relevant targets for innovative therapeutic approaches, as they
from tumor growth, to angiogenesis, to the recruitment of tumor-associated leucocytes, to the formation of
can regulate cancer cells and stromal cells in concomitant manner in the tumor microenvironment. In addition
distant metastases (e.g. J Exp Med, 2008; J Clin Invest, 2010; EMBO Mol Med, 2012), validating their relevance
to their role as semaphorin and VEGF receptors, we and others found that neuropilins represent receptor hubs
as targets for molecular therapy. Moreover, recent findings have revealed novel functions of the semaphorin co-
on the cell surface, controlling the function of multiple signaling cascades supporting tumor growth, such as
receptor Neuropilin-1 in the regulation of EGFR oncogene signalling (Cancer Res, 2012), as well as in the recru-
EGFR and integrins.
itment of tumor associated macrophages (Cancer Cell, 2013). To date (Jan 2015), Dr Tamagnone is author of
more than 70 papers published in peer-reviewed journals, with over 8000 citations, and has an H-index of 41.
Research achievements:
The laboratory has been working on several aspects of the research topic. We studied the function of Plexin-D1
and Neuropilin-1 receptors in cancer cells and in the tumor microenvironment, and found that they can play
multiple roles in cancer progression. For instance, oncogene addicted tumor cells use Nrp1 to uphold survival
signaling cascades in response to targeted therapies. Moreover, Nrp1 mediates Sema3A-dependent recruitment
and localization of tumor associated macrophages in hypoxic tumor areas, where they can deploy their pro-angiogenic and immune-suppressor activity. Beside secreted family members, transmembrane semaphorins are
also presently being investigated in the lab, such as Sema4C and Sema6A. We accomplished novel and exciting
results about their role in cancer cells, regulating their intrinsic metastatic potential and therapeutic response
to targeted therapies. The lab is also a leader in semaphorin research at the international level, contributing
expert know-how and reagents to frontline collaborative studies.
Conclusions and perspectives:
Selected references
Semaphorins and their receptors are novel and exciting players in cancer progression. By understanding the
Cagnoni G, Tamagnone L. Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression.
Oncogene 2014, 33:4795-802
specific role of different family members in human cancers, we could validate novel predictive markers of
progression or response to innovative targeted therapies. Moreover, certain semaphorins (and receptors) have
already been put forward as potential targets for functional interference approaches, aimed at regulating angiogenesis, cancer cell invasiveness and metastatic progression.
Tamagnone L, Rehman M. “To Die or Not to Die: Sema3E Rules the Game”. Cancer Cell. 2013, 24:695-709
Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G,Tamagnone L. Neuropilin-1-dependent
regulation of EGF-receptor signaling. Cancer Research 2012, 72:5801-11
Tamagnone L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer.
Cancer Cell. 2012, 22:145-52
12 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 13
Candiolo Cancer Institute
Research topic:
Dynamic control of cell adhesion:
‘normalization’ of tumor blood vessels
Guido Serini MD, PhD
Laboratory of Cell Adhesion Dynamics
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933508
Fax. +39.011.9933524
The pharmacological modulation of integrin function can be therapeutically exploited to improve the biodistribution of
anti-neoplastic drugs and counteract the hypoxia-driven metastatic dissemination of cancer cells
Team
Donatella Valdembri, Chiara Camillo, Noemi Gioelli, Giulia Mana, Chiara Sandri, Giulia Villari
Biographical Sketch:
Grasping the molecular basis of cell adhesion dynamics to design effective ‘vascular normalizing’ drugs for
Over the last two decades, Guido Serini has investigated the role of integrin-mediated cell adhesion in the
anti-cancer therapy.
control of tumor progression and angiogenesis. He firstly reported (Serini et al., J. Natl. Cancer Inst. 1996;
88:442- 44) how the neo-expression of alpha6-beta4 integrin, now well-known for its pro-metastatic activity,
Background:
as a hallmark of the transition of human benign adenomas into malignant carcinomas. He also demonstrated
Tumor blood vessels are structurally and functionally aberrant, thus hampering the delivery of anti-cancer drugs and
(Serini et al., J. Cell Biol. 1998; 142:873-881) how the generation of pro-invasive and pro-angiogenic cancer as-
causing hypoxia-driven metastatic dissemination. Normalizing the vasculature of tumors could hence sizably improve
sociated fibroblasts requires integrin-triggered signals. He then focused on the mechanisms that, by tuning the
anti-cancer therapy. The binding of vascular endothelial cells (ECs) to the extracellular matrix (ECM) is mediated by
conformational activation of integrins, control physiological angiogenesis and are disrupted in cancer, finally
integrins, a class of adhesive receptors that can assume active or inactive conformations, respectively characterized
resulting in hypoxia-driven metastatization. After reporting that autocrine VEGF is critical for integrin activation
by high or low affinity binding to ECM ligands. Blood fluid shear stress is the main determinant of normal vascular
and vascular network formation (Serini et al., EMBO J., 2003; 22:1771-1779), he showed for the first time how
architecture and function, its foremost outcomes being that of triggering integrin activation and fostering EC-to-ECM
endothelial class 3 semaphorins (SEMA3) signal through plexin receptors to inhibit integrins and allow vascular
adhesion. As a direct consequence, ECs modify their adhesive interactions and reciprocal positions in space, finally
morphogenesis (Serini et al., Nature 2003; 424:391-397). Next, together with Dr. Giraudo, he discovered that
giving rise to a remodeled, mature, and functional vascular tree. In this framework, inhibitors of integrin function
SEMA3A is present in endothelial cells of pre-malignant lesions, lost during tumor progression, and, when the-
should warrant a swift responsivity of EC-to-ECM adhesion to variations in blood flow-elicited forces. Therefore, phar-
rapeutically reintroduced, able to normalize the vasculature, inhibit tumor growth, and extend survival (J. Clin.
macological modulation of integrin function might be therapeutically exploited to ‘normalize’ the tumor vasculature.
Invest., 2009; 119:3356-3372). He recently unveiled how vascular morphogenesis relies not only on integrin
activation, but also on dedicated signaling pathways that control active integrin traffic back and forth from
Research achievements:
adhesion sites (PloS Biol. 2009, 7(1): e1000025; Cell Res. 2012; 22:1479-501; Curr. Opin. Cell Biol. 2012;
We have previously shown how: (i) the chemorepulsive guidance cue semaphorin 3A (Sema3A) and its receptors
24:582–591). He authored 58 papers in peer-reviewed journals and has an H-index of 28.
plexins and neuropilin-1 (Nrp1) allow correct vascular morphogenesis by negatively modulating the conformational activation of integrins and inducing active/ECM bound integrin endocytosis; (ii) the abrogation of Sema3Adependent integrin-inhibitory signals underpins the alterations that characterize tumor blood vessels; (iii) somatic
gene transfer of Sema3A restores the physiological inhibition of endothelial integrins and effectively prevents
cancer vascular abnormalities, thus improving the penetration of anti-neoplastic drugs and impairing metastases.
Stemming from these findings, over the last two years, we rationally designed, generated, and purified a molecular
variant of Sema3A protein that we dubbed Sema3A* and is endowed with a much higher (Kd 0.7 nM) affinity for
its major signaling receptor plexin A4. Fittingly, we found that, when compared to its wild type counterpart, Sema3A* displays much more robust biochemical and biological activities on cultured ECs. Finally, in collaboration
with the Laboratory of Transgenic Mouse Models of our Institute, we proved how intra peritoneal administration
of recombinant mutant Sema3A* protein in transgenic and orthotopic mouse models of pancreatic cancer effectively normalizes the tumor vasculature and impairs liver metastatization.
Conclusions and perspectives:
Our data provide evidence of how the negative pharmacological modulation of endothelial integrins by Sema3A
can be therapeutically exploited to improve the biodistribution of anti-neoplastic drugs and counteract the hypoxiadriven metastatic dissemination of cancer cells. It will therefore be crucial to further characterize the mechanisms
and molecular determinants responsible for: (i) the inhibition of integrin-dependent EC adhesion by Sema3A; (ii)
the selective Nrp1-dependent control of active integrin traffic in ECs.
14 | The mechanisms of cancer onset and progression
Selected references
Serini G, Bussolino F, Maione F, Giraudo E. Class 3 semaphorins: physiological vascular normalizing agents for anticancer therapy. J Intern Med. 2013, 273:138-55.
Valdembri D, Serini G. Regulation of adhesion site dynamics by integrin traffic. Curr. Opin. Cell Biol. 2012, 24:582-91
Maione F et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic
treatment in mice. J Clin Invest. 2012, 122:1832-48
Sandri C, et al. The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active
integrin endocytosis and Rac signaling. Cell Res. 2012, 22:1479-501
The mechanisms of cancer onset and progression | 15
Candiolo Cancer Institute
Research topic:
New targets for anti-angiogenic therapy
Enrico Giraudo PhD
Laboratory of Transgenic Mouse Models
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933505
Fax. +39.011.9933524
The better understanding of the anti-metastatic and normalizing effects of Sema3s on tumor blood vessels, will allow
design new strategies to overcome the resistance to anti-angiogenic therapy
Team
Federica Maione, Stefania Capano, Yaqu Qiu, Donatella Regano
Biographical Sketch:
Semaphorin 3A: a new tool to normalize the tumor vasculature and to halt metastasis formation.
Enrico Giraudo has contributed with a high quality track record of publications to the research field of tumor angiogenesis. Since the beginning, he has contributed to the identification of the molecular mechanisms
Background:
that regulate the motility and differentiation of angiogenic endothelial cells (Giraudo E. J. Biol. Chem, 1998;
Angiogenesis is required for invasive tumor growth and metastasis. It is well described that tumor vessel nor-
157:2618-23; Nature Med. 1996; 2:1371-75; Giraudo E. J Biol Chem. 2003; 278:50702-13). His main focus
malization represents a remarkably advantageous anti-cancer strategy, reducing tumor hypoxia and also being
has been the study of the mechanisms regulating tumor angiogenesis and cancer progression in transgenic
able to favor chemotherapy delivery and response to radiotherapy. It is critical therefore to identify new “pro-
mouse models of tumorigenesis. He described the molecular zip-code deciphering blood and lymphatic hete-
normalizing” modulators to define new anti-angiogenic combinatory regimens to block tumor growth. In these
rogeneity during tumorigenesis (Cancer Cell. 2003; 4:383-91). Next, he uncovered an important role of matrix
years, several studies have showe that class3 semaphorins (Sema3s), that act via receptor complexes binding
metallo-proteases (MMP)-9 and macrophages on tumor angiogenesis in a transgenic model of cervical cancer,
neuropilins 1 and 2 (Nrp1/2) and transducing the signal by plexins (Plxns), represent new targets to inhibit
by employing an amino-bisphosphonate Zoledronic acid able to efficiently inhibit cancer growth (Giraudo E. J
tumor angiogenesis and cancer growth.
Clin Invest. 2004; 114:623-33). More recently he first demonstrated that the axon guidance cue Semaphorin 3A
is an endogenous angiogenic inhibitor and that its therapeutically re-expression in cancers impairsangiogene-
Research achievements:
sis, tumor growth and induced vessel normalization in mouse models of cancer (Maione F. J Clin. Invest. 2009;
By using mouse models of spontaneous pancreatic tumors (RIP-Tag2) and cervical carcinomas (HPV16/E2) it
119:3356-72). On these bases, he showed that Sema3A was able to overcome resistance to anti-angiogenic
a role of Sema3A has been uncovered as an endogenous angiogenic inhibitor that impairs tumor growth and
therapies, by normalizing tumor vessels and inhibiting hypoxia (Maione F. J. Clin. Invest. 2012; 122:1832-48).
normalizes tumor vasculature. Interestingly, the treatment of mice with adeno-associate virus (AAV)-8 Sema3A
To date, he has authored 35 papers published in peer-reviewed journals..
counteracted Sunitinib- and DC101- induced resistance to therapy by normalizing the tumor vasculature. Studies aimed it better defining the mechanisms of action of Sema3A, unveiled that the treatment of RIP-Tag2
mice with Sema3A inhibited c-Met phosphorylation both in vessels in tumor cells. In co-culture systems of
human endothelial cells (ECs) and pericytes Sema3A attracted the pericytes toward ECs and down-modulated
Sema3A
Nrp-1 in both cell types, with the consequent over-expression of PDGF-B and Ang-1, known to promote vessel
maturation. Remarkably, Sema3A strongly inhibited HGF-induced Met phosphorylation in Nrp-1 silenced ECs,
suggesting that this molecule could act directly binding Met or HGF.
Notably, Sema3A impaired HGF-induced Met phosphorylation, not only in ECs, but also in several Nrp-1-silenced tumor cell lines and induced apoptosis similarly to the Met inhibitor JNJ-38877605. Finally the treatment
of a mouse model of pancreatic ductal adenocarcinoma (PDAC) with Sema3A revealed a significant reduction
of metastasis formation, a normalization of tumor vasculature and a selective impairment of Met phosphorylation both in vessels and in tumor cells.
Tumor vasculature
Normalized vasculature
Sema3A is a new anti-angiogenic and anti-metastatic molecule that is lost during tumor progression
and, when re-expressed normalizes the tumor vasculature and blocks tumor progression
Conclusions and perspectives:
Selected references
Based on these findings the main focus of research are the following: (i) investigation of the molecular mechani-
Serini G, et al. Class 3 semaphorins: physiological vascular normalizing agents for anti-cancer therapy.
J. Intern. Med. 2013, 273:138-55.
sms by which Sema3A turns off the HGF/Met pathway in different stroma cell types and cancer cells; (ii) study
of the ability of Sema3A to impair cancer dissemination in different Met-addicted tumor cells types in vivo; (iii)
evaluation of the anti-metastatic and pro-vessel normalizing effects of a non-proteolyzable high-affinity version
of Sema3A (in collaboration with the laboratory of Cell Adhesion Dynamics) in different mouse models of human tumors.
16 | The mechanisms of cancer onset and progression
Maione F,et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic
treatment in mice. J. Clin.Invest. 2012, 122:1832-48.
Meda C,et al. Sema4A exerts a pro-angiogenic effect by enhancing VEGF-A expression in macrophages.
J.Immunol. 2012, 188:4081-92
The mechanisms of cancer onset and progression | 17
Candiolo Cancer Institute
Research topic:
Role of membrane receptor endocytosis
in the dissemination of metastatic cells
Letizia Lanzetti PhD
Laboratory of Membrane Trafficking
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933508
Fax. +39.011.9933524
Knowing the mechanisms that control the downregulation of receptors involved in metastatic cell dissemination
provides the rationale for the generation of innovative anti -neoplastic drugs
Team
Emanuela Pupo, Nadia Ducano
Biographical Sketch:
Role of endocytosis in the regulation of signaling by oncogenic tyrosine kinase receptors.
Letizia Lanzetti did her training at the Department of Medical Genetic in Torino where she participated in the
isolation of a novel gene family: the endophilins. Next, she joined the European Institute of Oncology in Milan
Background:
to study the impact of endocytosis on the signal transduction cascade. Her work pioneered the existence of
Tumors, in order to grow and metastasize, activate pathways that largely depend on endocytic proteins as these
crosstalk between these processes as described in two of her major publications (Lanzetti et al., 2000, Nature
molecules control receptor tyrosine kinase (RTKs) signaling and cell migration/invasion. Although mutations in
408:374-7), (Lanzetti et al., 2004, Nature 429:309-14).
endocytic genes have crucial roles in the manifestation of the neoplastic phenotype, the possibility to exploit
In 2008 she established her laboratory at the Candiolo Cancer Institute. Here, she revealed a novel function for
endocytic proteins as targets of pharmacological intervention, alone or in combination with other treatments,
endocytic proteins in cancer cell division (PNAS 2011; 108:17337-42), and in cell migration and invasion (Curr.
are still poorly investigated. Work in our unit addresses the role of key endocytic players, the small GTPase
Biol. 2013; 23:2355-64).
Rab5 and its negative regulator RN-tre, as well as the effects of endocytosis inhibition, in the regulation of RTKs
Her work has led to the identification of molecular pathways that control signaling and trafficking of receptors
signaling and in cell invasion.
involved in cell transformation and invasion. Currently, she is widening her research looking at the feasibility of
targeting endocytic molecules, in combination with other treatments, in cancer therapy.
Research achievements:
Recently, we identified a novel molecular mechanism that prevents chemotactic cell migration of both normal
and cancer cells. Endocytosis controls the downregulation of phosphorylated RTKs. We found that inhibition of
cherry-RN-tre
GFP-paxillin
merge
the oncogenic MET kinase receptor by ATP-competitive drugs prevents receptor endocytosis resulting in MET
accumulation at the plasma membrane. After inhibitor removal, MET phosphorylation recovers to levels higher
than those displayed at steady-state and reactivates the downstream cascade. This generates a “rebound” effect
pushing quiescent cancer cells back into the cell cycle.
Conclusions and perspectives:
Database analyses has revealed that RN-tre is amplified/overexpressed in 16% of breast tumors. Based on its
function in receptor signaling and cell adhesion, we hypothesize that RN-tre overexpression in breast cancer cells
might confer proliferative advantages by upregulating oncogenic tyrosine kinase receptors, and/or promoting
anchorage-independent growth and cell survival. To determine the value of targeting RN-tre in breast cancer,
we will investigate whether its downregulation reduces the oncogenic potential of breast cancer cell lines that
RN-tre localizes to focal adhesions. Snapshot from Total Internal Fluorescence Microscopy in living RN-tre KO
fibroblasts expressing cherry-RN-tre (red) and the focal adhesion marker GFP-paxillin (green). Bar, 10 μm.
carry RN-tre amplification. Based on our findings on MET kinase inhibition, we plan to address the effects of
derailed endocytosis in tumor recurrence. We will study the rebound effects on proliferation of cancer cells that
were initially subjected to ATP-competitive RTK inhibitors and then released from the inhibition, trying to mimic
what might happen in patients treated with similar drugs in a time window. We will address whether alternate
Selected references
or metronomic treatment with RTKs inhibitors and therapeutic antibodies might counteract this harmful effect.
Palamidessi A, Frittoli E, Ducano N, Offenhauser N, Sigismund S, Kajiho H, Parazzoli D, Oldani A, Gobbi M, Serini
G, Di Fiore PP, Scita G, Lanzetti L. The GTPase-activating protein RN-tre controls focal adhesion turnover and cell
migration. Curr Biol. 2013, 23:2355-64.
Lanzetti L. A novel function of Rab5 in mitosis. Small GTPases. 2012, 3:168-72.
Serio G, Margaria V, Jensen S, Oldani A, Bartek J, Bussolino F, Lanzetti L. Small GTPase Rab5 participates in
chromosome congression and regulates localization of the centromere-associated protein CENP-F to kinetochores.
Proc Natl Acad Sci U S A. 2011, 108:17337-42
18 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 19
Candiolo Cancer Institute
Research topic:
From neuronal biology to neoplastic progression
Marco Arese PhD
Laboratory of Neurovascular Biology
Associate Professor of Biochemistry
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933847
Fax. +39.011.9933524
The identification of ‘molecular keys’ that mediate the relationship between tumor cells, blood vessels and nerves will
contribute to the definition of a new class of therapeutic targets
Team
Laura Bizzozzero, Margherita Pergolizzi, Elena Riccitelli, Grazia Vitagliano
Biographical Sketch:
Neuroligin: a novel modulator of cell transformation and cancer diffusion through nerves.
Marco Arese has dedicated his early research activities to the study of various mediators of intercellular communication that involve cancer and vascular cells ( J Clin Invest. 1995 Aug;96:940-52). In the laboratory of Prof.
Background:
Daniel B. Rifkin, at the New York University Medical Center (USA), he examined the mechanisms of action of
Neuroligin (NLGN) is a neuronal and tumoral adhesion protein that is a translational target of the mTOR (me-
two growth factors: Fibroblast Growth Factor-2 (FGF-2-. Mol Biol Cell. 1999 May;10: 1429-44) and transforming
chanistic target of rapamycin) kinase. mTOR plays a key role in tumorigenesis, but mTOR based therapies
growth factor-beta (TGF-beta ). During the last fifteen years, he has devoted himself to studying the “molecular
have had limited success, mainly because of evasive resistance and lack of predictive biomarkers of effi-
parallels” between the nervous system and vascular and tumoral tissues, with the aim of finding new targets that
cacy. Tumor-nerve interactions are a clinically significant but often underestimated way of cancer diffusion,
drive the cooperation between the tumor and its “microenvironment” (specifically, infiltrating vessels and nerves).
including colorectal cancer (CRC). Tumor and nerve relations take place by Perineural Invasion (PNI), the
In turn, this cooperation is known to fuel disease progression. Initially, he discovered that two synaptic proteins,
invasion of nearby nerves by cancer cells, and neo-neurogenesis, or the stimulation of neurite outgrowth by
Neurexin and Neuroligin, have widespread functions in the vascular system, including tumor angiogenesis (Proc
the cancer through soluble signals. These obviously represent different aspects of a wide range of molecular
Natl Acad Sci U S A. 2009 Dec 8;106:20782-7; Arterioscler Thromb Vasc Biol. 2012 Jul;32:1563-72). He is cur-
interactions that are nevertheless poorly defined. Moreover, no specific therapy exists that will target tumor
rently devolving all efforts to focusing on the role of these two nervous proteins in the tumor/nerves connections
nerve interactions, so new molecular players and therapies are needed. Ultimately, finding novel proteins that
, which mediate tumor growth and dissemination but are still widely underestimated in the clinic.
provide insight into the tumorigenic properties of mTOR both in the tumor cell itself and in the microenvironment, as well as serving as predictive biomarkers, is paramount.
Research achievements:
This laboratory has been working on the extra-neuronal activities of NLGN for the last ten years. Since 2013
we have focused on the following questions on the role of tumoral NLGN (mainly in CRC): (a) How does it impact tumor cell phenotypes? (b) Does it modulate PNI and neo-neurogenesis? (c) Does it influence the cancer
response (growth/invasion/PNI) to mTOR inhibition? The results obtained to date show that NLGN inhibits
tumor cell proliferation, anchorage independent growth and in vivo xenograft growth but promotes PNI. This
last effect is completely abolished by drug-mediated blockade of mTOR.
Conclusions and perspectives:
P​
rostate cancer cells ​
(left periphery)
invade a ​murine ​d​orsal r​​oot​ganglion with
its neurites​(center)
If broadly confirmed, our data reveal NLGN as a double-faced cue (i.e. growth suppressing but pro- invasive)
that is targeted by an existing anti-tumoral drug, hence carrying potential clinical implications. We now want
to exploit the knowledge coming from the neuronal field, the large amount of reagents present in this laboratory, and in vitro and in vivo experimental settings (mouse xeno- and ortho- transplants) in order to fully
answer the questions stated above.
Selected references
Samarelli AV, et all. Neuroligin 1 induces blood vessel maturation by cooperating with the α6 integrin.
The Journal of biological chemistry. 2014, 289:19466-76
Rissone A, et al. The synaptic proteins neurexin and neuroligin synergize with extracellular matrix-binding vascular
endothelial growth factor a during zebrafish vascular development.
Arterioscler Thromb Vasc. Biol. 2012, 32:1563-72.
Bottos A, Rissone A, Bussolino F, Arese M. Neurexins and neuroligins: synapses look out of the nervous system.
Cell Mol Life Sci. 2011, 68:2655-66.
20 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 21
Candiolo Cancer Institute
Research topic:
Cellular and molecular mechanisms sustaining tumor angiogenesis
Federico Bussolino MD
Laboratory of Vascular Oncology
Full Professor of Biochemistry
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933347
Fax. +39.011.9933524
All target therapies, including antiangiogenic therapies, are far from the wished results. However antiangiogenic
regimens are an important tool for solid tumor treatment. Our studies aim at understanding the complexity of
angiogenic processes in physiology
Team
Serena Marchiò, Elena Astanina, Valentina Comunanza, Gabriella Doronzo, Lucia Napione, Alessio Noghero,
Davide Corà, Maria Alvaro, Anna Gualandris
Biographical Sketch:
Identification of early biomarkers of pancreatic ductal carcinoma (PDAC).
Federico Bussolino began his scientific career by investigating the cross-talks between the mediators of inflammation and vascular cells with the goal of understanding the cellular traffic across vascular walls. Then (1988), he
Background:
was captured by the discovery of colony stimulating factors and their strict specificity during hematopoiesis. He
Elegant tracking studies of the genetic evolution of PDACs indicate at least 15 years between the occurrence of
has gone beyond this concept, showing that these molecules activate a pro-survival and pro-angiogenic program in
the initiating mutation and the acquisition of metastatic ability. This result demonstrates a broad time window
endothelial cells (Nature 337: 471, 1989). After 20 years, the proangiogenic roles of these molecules have clarified
of opportunity for early detection to prevent deaths from metastatic disease. We reasoned that an early biomar-
their fundamental role in the bone marrow vascular niche, which is fundamental in the maturation of blood cells.
ker had to play a necessary role in the onset of the disease and preferentially released from the cells. Therefore
Then he moved to tumor angiogenesis showing the role of the MET receptor in cancer-associated vascularization (J
we performed a whole transcriptomic analysis of the early in situ carcinomas (PanIn) isolated by laser capture
Cell Biol 119: 629, 1992). This seminal observation supported the concept that Met is pivotal in the regulating the
microdissection from a genetically engineered mouse model characterized by the expression of KRASG12V in
cancer invasive growth. In 1996, he began to work on VEGFs showing that HIV-1 Tat activates the VEGF pathway.
acinar cells through the use of the elastase promoter (Elas-K-RasG12V).
This result emphasizes the ability of the virus to directly support the progression of tumors appearing in AIDS (Nat
Med. 2:1371, 1996; Nat Med 8:225,2002). In Embo J. (18: 882,1999), he firstly demonstrated the existence of a
Research achievements:
dynamic platform constituted by adhesive and tyrosine-kinase receptors. In 2003, he funded a successful interdi-
RNAs highly expressed in PanIn encode proteins involved in axon guidance cues and synaptogenesis that re-
sciplinary PhD program on complexity in biology that has anticipated the concepts of Systems Biology. In 2003,
cently have been demonstrated to be altered in PDAC. We focused on neuroligins (Nlg), a family of adhesive
he contributed to open a frontier in angiogenesis, by connecting the 3D architecture of the vascular bed with the
molecules regulating synaptic activity. Anti-pan-Nlgs antibody showed a faintl membrane signal of acinar and
mechanisms that wire neurons. (Nature 424: 391, 2003). Recently, he has added another piece of information
ductal cells whereas PanINs displayed a stronger staining that dropped in PDAC. Similar results were obtained
about the cues shared by the brain and vascular system by demonstrating that two synaptic proteins, neurexin and
in human lesions (a series of 6 PanIn, 8 PDAC and 4 pancreatitis from the University of Verona). By analysing
neuroligin, regulate the assembly of vascular units.
the expression of the 5 Nlgs we visualized a minute population of acinar cells carrying KRasG12V and expressing Nlg-2 associated with stemness markers (DCLK1, CD24, CD44, and CXCR4). The current hypothesis of
the pathogenesis of PDAC relies on the differentiation of acinar precursors carrying KRAS mutation into ductal
cells (acinar-ductal metaplasia). We demonstrated that KRasG12V acinar cells isolated from Elas-KRasG12V
underwent in vitro acinar ductal metaplasia with an increased expression of Nlg-2. An isogenic cell line carrying
KRasG12V (provided by Prof. Bardelli) overexpressed Nlg-2 as compared with wild-type cells. Loss-of-function
experiments showed that Nlg-2 ablation halted acinar-ductal metaplasia, supporting the concept that Nlg-2
is necessary in the early phase of PDAC. Then, we looked for the possibility that Nlg-2 was shed by the cells,
supported by the presence of a Disintegrin And Metalloproteinase (ADAM) proteolytic cleavage site in the extracellular domain. Nlg-2 accumulated in the serum-free supernatant of pancreatic PT45 human cell line overexpressing Nlg-2. This phenomenon is blocked by ADAM inhibitors TAPE-2 and GM 6001.
Selected references
Conclusions and perspectives:
We reported that Nlg2 (i) has an early role in PDAC by promoting the acinar-ductal metaplasia of precursors; (ii) is
shed by an ADAM-dependent mechanism. To further support the role of Nlg2 as an early biomarker in PDAC, we will
continue the following activities: (i) demonstration of the role of Nlg-2 in stemness features of acinar precursors
undergoing acinar-ductal metaplasia; (ii) analysis of PDAC progression in Elas-K-RasG12V model crossed-back with
Nlg-2-/- mice (in collaboration with Prof. Arese); (iii) generation of mAb anti-Nlg2 to set-up an ELISA for Nlg-2 quantification in biological fluids; (iv) increase of human samples to analyse Nlg-2 expression and activities.
22 | The mechanisms of cancer onset and progression
Bussolino F, Giraudo E, Serini G. Class 3 semaphorin in angiogenesis and lymphangiogenesis.
Chem Immunol Allergy. 2014, 99:71-88
Corà D, Astanina E, Giraudo E, Bussolino F. Semaphorins in cardiovascular medicine.
Trends Mol Med. 2014 Oct;20:589-98.
Marchiò S, Astanina E, Bussolino F. Emerging lymphae for the fountain of life. EMBO J. 2013,32:609-11
Napione L et al. IL-12-dependent innate immunity arrests endothelial cells in G0-G1 phase by a p21(Cip1/Waf1)
mediated mechanism. Angiogenesis. 2012, 15:713-25
The mechanisms of cancer onset and progression | 23
Candiolo Cancer Institute
Research topic:
Cell migration in tumor angiogenesis and invasion
Luca Primo PhD
Laboratory of Cell Migration
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933505
Fax. +39.011.9933524
The identification of molecular mechanisms involved in tumor cell migration will allow the prevention of metastatic
dissemination by pharmacological inhibition
Team
Laura Di Blasio, Alberto Puliafito, Giulia Chiaverina, Paolo Gagliardi, Desiana Somale
Biographical Sketch:
Molecular mechanisms that differentiate invasive cancer cells from their non-motile counterparts, and the rela-
Luca Primo has a remarkable experience in the field of vascular cell biology. He started his research experience
tionship between tumor and non-tumor cells during cell migration.
characterizing the thrombospondin receptor CD36. He showed that this membrane protein was involved in the
pathogenesis of cerebral malaria (Blood, 1993; J Immunol, 2001) and angiogenesis (Faseb J., 2005) During
Background:
his post-doc he contributed to unveil the molecular mechanisms of several angiogenic growth factors, such as
Cancer cells spread from the initial site of tumor growth acquiring an invasive phenotype characterized by both
VEGF-A (JBiolChem, 1998) and GM-CSF (Blood, 1997). He then moved to the Candiolo Cancer Institute where
the loss of cell-cell interactions and increased cell motility. Cells which undergo this epithelial to mesenchymal
he focused his research efforts on the PI3K signalling pathway in angiogenesis and cell motility (Oncogene,
transition are then able to move and spread throughout the entire body as isolated and highly motile cells. Re-
2000). During a research experience at the Tuft University of Boston, he started to study the protein kinase
cent evidence shows that tumor cells also move as groups both in normal development and in cancer models,
PDK1, a downstream effector of PI3K. He discovered the central role of PDK1 in cell directional motility (JCell-
in a process named collective migration. Even vascular endothelial cells collectively migrate into tumor mass
Biol, 2007) and he elucidated the function PDK1 in breast cancer growth (Neoplasia, 2012) and invasion (JCell-
forming new vessels in a process called tumor angiogenesis.
Biol, 2014). By gene expression analysis in endothelial cells he discovered the pro-angiogenic role of integrin
a6 (Cancer Res, 2010) and the effects of
miR126 on Angiopoietin1 signaling (BBA-MolCellRes, 2012). Moreo-
Research achievements:
ver, he developed a new model for the three-dimensional study of tumor angiogenesis, the Human Arterial Ring
We are developing new three-dimensional (3D) culture systems that in combination with conventional cell bio-
assay, which can be exploited for drug screening and gene function analysis on human vessels (Blood, 2013).
logy approaches, allow the study of collective and directional cell migration. A new model for in vitro tumor
More recently, he described regulatory mechanisms of integrin endocytosis (Traffic, 2010; JCellSci, 2015) and
angiogenesis studies has been described and cell spheroid cultures from breast and prostate cell lines have
the role of endothelial podosomes in angiogenesis (NatCellBiol, 2014). Luca Primo is Associate Professor of
been developed. With these three-dimensional models we have been able to discover new mechanisms of PI3K
Biochemistry and group leader of the Laboratory of Cell Migration. He is author of more than 40 papers pu-
regulation of collective migration and the role of the endothelial podosome in tumor angiogenesis.
blished in peer-reviewed journals, with an H-index of 23.
Conclusions and perspectives:
We are convinced that spheroids/organoids 3D culture from cells and tissues could overcome limitations of
established cell lines, such as adaptation to 2D growth, providing better models for studying collective migration, epithelial-to mesenchymal transition and tumor vascularization, and for the identification of molecular
mechanisms involved in these processes. Moreover, we are establishing 3D cell cultures from patient-derived
xenograft (PDX) of colon cancer with a high percentage of in vitro engraftment. By combining our know-how
in 3D cultures with the PDX platform developed in the Institute, we will implement an unprecedented in vitro
platform for genetic functional and drug screening purposes.
DCIS invasive spheroid
Selected references
Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Puliafito A, Bouvard C, Sessa R, Tarone G, Sorokin L, Helley D, Jain RK,
Serini G, Bussolino F, Primo L. Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis.
Nature Cell Biology. 2014. 16: 931-41
Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Sessa R, Bussolino F, Primo L. Modeling human tumor angiogenesis
in a three-dimensional culture system. Blood. 2013, 121:129-37
Gagliardi PA, et al. Phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Aktindependent manner. Neoplasia. 2012, 14:719-31.
24 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 25
Candiolo Cancer Institute
Research topic:
Mechanisms of escape from anti-angiogenic therapy
Paolo Michieli PhD
Laboratory of Cancer Metabolism
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933219
Fax. +39.011.9933225
The development of novel approaches such as anti-metabolic therapy can open new avenues for the treatment of
aggressive forms of colorectal cancer
Team
Manuela Cazzanti, Federica Linty, Alessia Mira, Virginia Morello
Biographical Sketch:
Opportunities and limitations of targeting the HGF/MET pathway for cancer therapy.
Paolo Michieli graduated in Biological Sciences at the University of Milano in 1990. After a few years of training
at the Mario Negri Institute for Pharmacological Research and the Istituto Nazionale dei Tumori, both in Milano,
Background:
he carried out his post-doc in the Laboratory of Cellular and Molecular Biology at the National Cancer Institute
HGF and MET have been attracting increasing interest in the last two decades as appealing targets for cancer the-
in Bethesda, Maryland. During this period he contributed to several scientific publications in the field of on-
rapy, leading to the development of various targeted drugs. However, the initial enthusiasm has been partially mi-
cogenes, growth factors and cell cycle. In 1997 he moved back to Italy to the newly founded Candiolo Cancer
tigated by a number of realizations: (i) anti-HGF/MET drugs display cytostatic rather than cytotoxic activity even
Institute in Candiolo, Torino. Since then he has been Group Leader of a small team committed to experimenting
in the most MET-dependent systems; (ii) MET activation in cancer occurs through multiple and redundant mecha-
novel therapeutic strategies in oncology, with particular reference to the molecular targeting of growth factors
nisms, often involving micro environmental signals; (iii) the patient population that can benefit from HGF/MET
and their receptors. In 2001 he specialized in Clinical Pathology at the University of Torino Medical School.
inhibition per se is less broad than anticipated. To date, no HGF or MET targeted drug is approved for clinical use.
In 2008 he received a Ph.D. in Cellular Sciences and Technologies from the same University, and in December
2011 he was appointed tenured Assistant Professor at the Department of Oncology. He is author of 36 scien-
Research achievements:
tific publications accounting for more than 4,000 citations, a total impact factor of 387, an H-index of 26 and
(i) Mechanism of action of tivantinib. Tivantinib is being tested in Phase III as a ‘highly selective MET inhibitor’.
a i10-index of 30.
We demonstrated that this drug is not a MET inhibitor at all but a microtubule active cytotoxic compound. (ii)
Generation of antagonistic anti MET antibodies for cancer therapy. Using the SIMPLETM antibody platform and
in collaboration with arGEN X BVBA (Zwijnaarde, Belgium), we generated and validated 68 different antagonistic anti MET antibodies. The most promising among them was selected for clinical development and is now in
Phase I (clinicaltrial.gov ID #NCT02055066). (iii) Role of HGF/MET signaling in intrinsic and acquired resistance to targeted therapies. We have demonstrated that micro environment derived HGF plays a major role in the
resistance to anti angiogenic, anti MET and anti MEK therapies. (iv) Gene therapy of cancer using a monovalent
anti MET antibody. We had previously demonstrated in collaboration with the Laboratory of Gene Therapy that
the DN 30 anti MET antibody is antagonistic only if in a monovalent form. To achieve delivery of DN 30 Fab to
the tumor, a lentiviral vector based technique was employed.
Conclusions and perspectives:
The HGF/MET pathway remains an appealing but elusive target for cancer therapy. While several HGF/MET
inhibitors are available with therapeutic potential, including those generated by this laboratory, their optimal
employment has not been focused yet. Our results point at an important role of HGF as a master modulator
of cancer cell survival and metabolism in adverse micro environmental conditions, suggesting a potential therapeutic strategy based on the association of HGF MET inhibitors with drugs that cause tumor energetic unba-
Selected references
lance. Among the most interesting drugs of this kind are anti metabolic agents, which held promise for cancer
Basilico C et al. Four individually druggable MET hotspots mediate HGF-driven tumor progression. The Journal of
clinical investigation. 2014, 124:3172-86.
therapy in combination with HGF/MET targeted drugs. This field of study is currently being actively investigated
by this laboratory, particularly in colorectal cancer.
Pennacchietti S, Cazzanti M, Bertotti A, Rideout WM 3rd, Han M, Gyuris J, Perera T, Comoglio PM, Trusolino L,
Michieli P. Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs.
Cancer Research 2014, 74:6598-609.
Michieli P, Di Nicolantonio F. Targeted therapies: Tivantinib - a cytotoxic drug in MET inhibitor’s clothes ?
Nat Rev Clin Oncol. 2013, 10:372-4.
26 | The mechanisms of cancer onset and progression
The mechanisms of cancer onset and progression | 27
Candiolo Cancer Institute
Research topic:
Research topic 2
From Molecular Biology to “Precision Medicine”
Research topic 2 is the scientific core on which the projects of most laboratories of the Institute are focused.
Advances in genome sequencing and expression analysis have made it possible to quickly identify genetic
alterations with a potential “driver” role in tumor development, with unprecedented informative power. Thanks
to these studies, today it is possible to classify tumors, not only on the basis of their site of origin and
histopathological features, but also – and especially – by the identification of the genetic lesions that support
their growth and that, for this reason, provoke tumor death when deactivated by targeted therapies. However,
the contribution of each lesion to the transformed phenotype remains elusive. Moreover, knowledge is still
insufficient on the mechanisms that control the lack of response to targeted therapies, even in the presence of a
molecular target (primary resistance), as well as on the mechanisms that lead to progressive attenuation of the
response after prolonged treatment (acquired resistance). Translational Research is a multi-disciplinary task
based on the expertise of a new generation of scientists, specifically trained to translate molecular information
into more effective treatments. The goals are ambitious: to integrate the traditional prognostic and diagnostic
factors with a very detailed characterization of the genetic and functional alterations of the tumor; to identify
new malfunctioning regulatory pathways in cancer; to isolate and study cancer stem cells; to develop new
preclinical platforms that can reliably disclose – and understand in detail – the prospective results of clinical
practice. The generation of this kind of knowledge is instrumental to instructing clinical trials that will be no
longer based on empirical information but on a strong rational connotation.
Research Topic 2 concerns:
2.1. Oncogenes and growth factors
2.2. Genes responsible for response to antineoplastic drugs
2.3. Preclinical models of “personalized” therapies
2.4. Resistance to targeted therapies
Eaglets braistorm, few years ago...
28 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 29
Oncogenes involved in invasive growth
Paolo Comoglio MD, PhD
Laboratory of Exploratory Research
Full Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933601
Fax. +39.011.962.1525
Genetic and molecular biology beyond the metastatic process is largely unknown. It is mandatory to identify and to
validate therapeutic targets to develop long-sought (and still missing) effective therapies
Team
Cristina Basilico, Silvia Benvenuti, Alessandra Gentile, Federica Verginelli, Maria Rita Virzì, Chiara Modica
Biographical Sketch
Oncogenes involved in invasive growth
Paolo Comoglio has a long and distinguished record in the field of research on tyrosine kinase receptors and
related oncogenes. He developed the first anti-phosphotyrosine antibody (Comoglio et al. 1984, EMBO J. 3:483-
Background:
9); by this tool he identified the tyrosine kinase encoded by the rearranged Bcr-Abl oncogene, responsible for
Growing evidence prompted us to hypothesize that the metastatic process involves members of the gene
the onset of Chronic Myeloid Leukemia (Mol Cell Biol. 1986; 6:1803-11.)
‘super-family’ of tyrosine kinase receptors for ‘scatter factor’, homologues to the Met oncogene (Ron, Axl, Mer
He focused his research efforts on the full mechanistic insight of the genetics, biochemistry and biology of
and Tyro). Recently, other poorly characterized genes of the family have been identified, Ror1 and Ror2, that can
the Met receptor, with a special emphasis on the role of this oncogene in human cancers. After a long standing
possibly interfere with the response to drugs directed against Met (entered in the clinic), generating resistance.
career he is now acknowledged as a leader in the field.
He identified the tyrosine kinase receptor encoded by the Met oncogene (Nature. 1989; 339:155-6.), discovered
Research achievements:
that Hepatocyte Growth Factor (HGF) is the cognate ligand (Oncogene. 1991; 6:501-4.) ) and cloned the Plexin
In the past we have shown that the Met oncogene encodes the receptor for the ‘scatter factor’ HGF. A series of
genes (Cell. 1999; 99:71-80), recognizing their role as receptors for Semaphorins, signals for cell-cell repelling
studies –performed for two decades in this and other laboratories- revealed the involvement and the importan-
clues.
ce of this oncogene in human cancers, demonstrating its key role in the control of ‘invasive growth’, a genetic
He identified and elucidated the functions of two tyrosine kinase receptors, encoded by genes structurally rela-
program driving the metastatic process. We contributed to the development of drugs that inactivate the Met
ted to Met : Ron, (EMBO J. 1994; 13:3524-32), and Ror ( Cancer Res. 2011; 71:3132-41).
tyrosine kinase: either chemical inhibitors or monoclonal antibodies. These drugs inactivate cancer stem cells
On the translational front he generated the anti-Met antibody DN30, and its monovalent counterpart, to be used
in preclinical models of glioblastoma, colorectal and gastric carcinomas, and provide promising results in cli-
in cancer therapy, either conventional or by ‘gene transfer’ (Cancer Res. 2008; 68: 9176-83).
nical trials.
Paolo Comoglio expounded and introduced a number of
wisdoms that are now largely accepted and wide-
spread, notably the concept of ‘invasive growth’, a genetic program otherwise ‘physiological’ but ‘usurped’ by
Conclusions and perspectives:
cancer cells to progress toward metastasis (Nature Rev. Cancer 2002, 2:289-300)
We are now working on the characterization of tyrosine kinase receptors of the Met oncogene family (Ron, Axl,
To date (Dec 2014), he is author of more than 350 papers published in peer-reviewed journals generating more
Mer and Tyro, Ror1-2) at the genetic, biochemical and functional levels. In particular, we are studying their pos-
than 25.000 citations.
sible interference -positive or negative- with the intracellular signaling triggered by Met during execution of the
invasive growth program. Emphasis is given to the study of a hyper-metastatic syndrome, the so-called CUP,
metastatic cancer from unknown primary origin.
Selected references
Boccaccio C, Comoglio PM. MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure.
Curr Opin Cell Biol. 2014 31:98-105.
Boccaccio C, Luraghi P, Comoglio PM. MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal
cancer stem cells. Cancer Research. 2014. 74:3647-51
Benvenuti S, Gentile A, Lazzari L, Arnesano A, Trusolino L, Comoglio PM. An ‘in-cell trial’ to assess the efficacy of a
monovalent anti-MET antibody as monotherapy and in association with standard cytotoxics. Mol Oncol. 2014, 8:378-88
30 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 31
Candiolo Cancer Institute
Research topic:
Preclinical models of oncogene ‘addiction’
Livio Trusolino MD
Laboratory of Precision Medicine
Associate Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933202
Fax. +39.011.9933225
We aim to identify ‘dominant’ genetic aberrations that drive tumorigenesis and put them in the context of concurrent
‘recessive’ alterations that may act as modifiers of response to targeted therapies
Team
Andrea Bertotti, Barbara Lupo, Francesco Galimi, Francesco Sassi, Giorgia Migliardi, Francesca Cottino,
Simonetta Maria Leto, Eugenia Zanella
Biographical Sketch:
Translational models of cancer precision medicine.
Since 2006, Livio Trusolino has been Associate Professor of Histology at the University of Turin Medical School,
Italy. He received his M.D. (1993) from the University of Turin and a Ph.D. in Human Oncology (1997) from the
Background:
San Raffaele Scientific Institute, Milan, Italy.
Advances in technologies have allowed the attainment of powerful insights into the molecular determinants of
Livio initially studied the cross-talk between growth factor receptors and adhesion molecules in tumour tran-
human tumours, and in many cases inactivation of individual oncogenic drivers results in tumor regression.
sformation and cancer progression. Later, his work concentrated on the characterisation of the molecular
However, this knowledge has been translated into effective treatments very slowly, due to difficulty in predicting
mechanisms underlying responsiveness to anti-cancer targeted therapies, using innovative preclinical models.
how the complex mutational background and the adaptive resilience of cancer cells can influence the activity
The results of Livio’s research have been published in leading journals such as Cell, Nature Genetics, Science
of the dominant oncogene and modify response to therapies.
Translational Medicine, and Cancer Discovery. He has also written review articles for Nature Reviews Drug Discovery, Nature Reviews Cancer, and Nature Reviews Molecular and Cellular Biology.
Research achievements:
Our projects aim at exploring the mechanisms of tumor dependency on oncogenic drivers and how such dependency is affected by genomic or functional modifiers, with an emphasis on colorectal cancer (CRC). Our
experimental pipeline entails the deployment of multi-dimensional data for discovery and hypothesis validation,
followed by cell-based mechanistic investigation and preclinical validation in patient-derived tumorgrafts – ’xenopatients’. By this approach, we have contributed to finding that hyperactivation of the HER2 and MET oncogenes correlate with resistance to anti-EGFR therapies (cetuximab and panitumumab). To examine the global
effects of somatic genetic changes in CRC on sensitivity to EGFR-targeted therapies, we performed complete
exome sequence and copy number analyses of 129 tumors and analyzed their response to anti-EGFR blockade
in xenopatients. We identified several alterations as potential mechanisms of resistance to this therapy as well
as genetic lesions segregating in tumors with increased sensitivity to anti-EGFR therapy. Resistance to EGFR
blockade could be overcome in xenopatients through combinatorial therapies targeting actionable genes. A typical response of CRC patients sensitive to EGFR neutralization is stable disease rather than massive regression.
Mining of candidate gene expression outliers – coupled with retrospective analysis of patient material and in
vitro functional studies – identified IGF2 as a predictor of poor sensitivity to cetuximab and as a new target. One
limitation of xenopatients is that human tumour stroma is substituted by host (murine) components. However,
this drawback can be exploited analytically to dissect the representation of human (cancer-cell specific) versus
mouse (stromal-cell specific) traits in CRCs. By doing so, we contributed to re-categorising the transcriptional
Waterfall plot of response to the anti-EGFR antibody cetuximab after 3 weeks of treatment,
compared with tumor volume at baseline, in a population of quadruple negative xenopatient cases.
5 models with HER2 amplification (red) and 2 models with MET amplification (orange) proved to
be resistant to EGFR blockade.
classification of CRC by demonstrating that a subtype displaying features of epithelial-to-mesenchymal transition and poor prognosis is not an expression of aggressive cancer cell dedifferentiation (as originally argued)
Selected references
but rather a read-out of abundant stromal content.
Hidalgo M et al. Patient-derived xenograft models: an emerging platform for translational cancer research.
Cancer Discov. 2014, 4:998-1013.
Conclusions and perspectives:
Bardelli et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discov. 2013, 3:658-73
Our studies provide a systematic functional approach to evaluate response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and provide a new vocabulary for the
molecular management of colorectal cancer with immediate clinical implications.
32 | From Molecular Biology to “Precision Medicine”
Bertotti A, Trusolino L. From bench to bedside: does preclinical practice in translational oncology need some
rebuilding? J Natl Cancer Inst. 2013, 105:1426-7.
From Molecular Biology to “Precision Medicine” | 33
Candiolo Cancer Institute
Research topic:
The puzzling oncosuppressive function of oncogenes
Maria Flavia Di Renzo MD
Laboratory of Cancer Genetics
Full Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933343
Fax. +39.011.9933524
Identification of novel therapeutic targets and predictive biomarkers responsive to chemotherapy or
targeted drugs in ovarian cancer
Team
Annalisa Lorenzato, Martina Olivero, Jessica Erriquez, Daniele Musiani, John David Konda, Erica Torchiaro
Biographical Sketch:
Unleashing the intrinsic tumor suppressive properties of oncogenes to kill cancer cells.
Maria Flavia Di Renzo got an MD degree at the University of Torino Medical School in 1977 and then the residency in Neurology in 1981. Besides short periods spent working in another University and abroad, she has
Background:
been working in the same University as professor since 1981 and as full professor of Histology since 1994 to
Oncogenic tyrosine kinases (TKs) might harbor intrinsic tumor suppressive functions. They sit at the apex of
date. In 1997 she became head of the Laboratory of Cancer Genetics of the Candiolo Cancer Institute.
multiple downstream signaling pathways that exert various biological effects depending upon cell type and
Since 1981 she has been involved in the study of oncogenes and tumor suppressor genes in human cancer with
context. While some of these pathways are mitogenic and pro-survival, others might restrain the oncogenic
a particular focus on tyrosine kinase oncogenes, demonstrating for the first time the increased expression of
potential by promoting, for example, apoptosis and senescence. Obviously, the latter programs do not confer
the MET oncogenes in human cancer (Di Renzo et al, Oncogene 1991 and subsequent publications). Moreover,
a selective advantage and thus are hidden in cancer cells. However, intrinsic tumor suppression of TKs might
she identified mutations of the MET oncogene in lymph node metastases of head and neck squamous cell car-
be unleashed to kill cancer cells. This Laboratory had demonstrated that activation of the MET TK by its ligand
cinomas, reinforcing the concept of a genetic basis of the cancer progression towards metastasis.
Hepatocyte Growth Factor (HGF) results in the commitment to death of ovarian cancer cells. This model has
In 2004 her major research interest turned in the study of human ovarian cancer with the aim of identifying
been exploited to identify actionable molecules, that could be targeted to treat ovarian cancer and to sensitize
suitable targets for molecular therapy. For this purpose the group led by Maria Flavia Di Renzo has used fun-
ovarian cancer to standard platinum and taxane based treatment, once they have developed resistance.
ctional (Rasola et al, Cancer Res 2004; Bardella et al., Clin. Cancer res 2007), genomic (Olivero et al., Mol.
Cancer Ther., 2006; Lorenzato et al., FASEB J 2012) and proteomic approaches (Musiani et al. FASEB J and J
Research achievements:
Proteome Res 2014), that have led to the identification of possibly actionable molecules.
Among the actionable molecules this laboratory has identified (i) CDT2, (ii) the small heat shock protein of
27 Kda (HSP27), (iii) the PIM 2 kinase and (iv) the 90 kDa ribosomal S6 kinases (RSKs) that is presently still
under investigation. In detail, using transcriptomic and small scale proteomics we found that MET activation in
ovarian cancer cells resulted in the down regulation of the anti-apoptotic small heat shock protein of 27 KDa
(HSP27, HSPB1) while MET inhibition in addicted cancer cell lines resulted in the increase of HSP27 and cell
protection from death. Likewise, in human cancer cells susceptible to EGFR inhibition, EGFR inhibitors induced
HSP27 expression and were strengthened by HSP27 suppression. Therefore, in cancer therapies targeting the
MET pathway, the induction of HSP27 might limit the efficacy of anti-MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction
of HSP27 by targeted agents might strongly impact the success of combination treatments. A SILAC-based
approach combined with TiO2-based phosphopeptide enrichment allowed the identification of PIM2 as a kinase
whose phosphorylation is regulated by DNA damaging agents in ovarian cancer cell lines. Targeting PIM2 kinase
sensitized ovarian cancer cells to drug-induced apoptosis, while PIM2 over-expression resulted in cell resistance
to DNA damaging agents.
Selected references
Conclusions and perspectives:
Altogether data showed that pro-apoptotic pathways can be unveiled in cancer cells by studying the unexpected
pro-death outcome of MET activation. This allowed the identification of actionable molecules for which inhibitors are available and may find clinical application as an alternative or an adjunct to standard chemotherapy.
Pavan S, et al. HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor.
Int J Cancer. 2014, 134:1289-99.
Lorenzato A, et al. AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional
activation in ovarian cancer cells. Exp Cell Res. 2013, 319:2627-36.
Pavan S, Olivero M, Corà D, Di Renzo MF. IRF-1 expression is induced by cisplatin in ovarian cancer cells and limits
drug effectiveness. Eur J Cancer. 2013, 49:964-73.
34 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 35
Candiolo Cancer Institute
Research topic:
Cancer stem cells and resistance to standard
and targeted therapies
Carla Boccaccio MD
Laboratory of Cancer Stem Cells Research
Associate Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933208
Fax. +39.011.9933225
To set up therapies targeted at ‘cancer stem cells’, that are cells that constitute the ‘roots of tumors’, that resist
chemo- and radio-therapy, and, after these conventional treatments, can cause tumor relapse
Team
Francesca De Bacco, Paolo Luraghi, Federica Verginelli, Viola Bigatto, Antonio D’Ambrosio, Francesca Orzan,
Raffaella Albano, Elena Casanova, Elia Cipriano, Roberta Neggia, Gigliola Reato
Biographical Sketch:
The MET oncogene in cancer stem cell resistance to standard and targeted therapies.
From the beginning of her career, Carla Boccaccio has contributed to elucidate the signalling and transcriptional mechanisms by which the MET oncogene controls invasive growth, a physiological program of stem
Background:
and progenitor cells, inappropriately activated during tumor onset and progression. She discovered that MET
Like normal tissues, tumors such as colorectal cancer or glioblastoma are structured according to a hierarchy
regulates a genetic program concomitantly driving a procoagulant and a neoplastic phenotype, thus helping to
that includes two main components. At the hierarchy’s apex there is a (small) subpopulation of ‘cancer stem
unravel the pathogenesis of Trousseau’s syndrome, the association of cancer and thrombosis frequently obser-
cells’ (CSC) able to self-renew, namely to proliferate endlessly, and to relentlessly support tumor regeneration,
ved, but often unexplained, in patients. More recently she discovered that MET is a functional marker of cancer
growth, and dissemination. At the hierarchy’s base there is an (ample) subpopulation of cells that, unlike CSC,
stem cells isolated from brain and colorectal tumors. In these cells, MET sustains self-renewal, invasion, and
have limited proliferative ability, and tend to aberrantly differentiate and die. This model implies that, to cure
resistance against DNA damaging treatments, such as ionizing radiation, and biological agents targeting other
the tumor, CSC must be eradicated. This task is challenging, as CSC are often inherently resistant to thera-
tyrosine kinase receptors such as EGFR. She is now engaged in understanding the interactions among MET
pies that so far have proven effective against the hierarchical basis of tumor cells, therapies that also include
activity, the genetic lesions occurring in cancer stem cells, and the cellular response to standard and targeted
the most innovative agents, targeted at the molecular lesions responsible for cancer pathogenesis. To achieve
treatments, to identify the clinical context where MET inhibition can be effective.
better therapeutic outcomes, it is mandatory to identify and attack the molecular and genetic mechanisms underlying CSC resistance to conventional chemo- and radio-therapy, or to agents targeted at molecular lesions.
Research achievements:
In CSC isolated from human metastatic colorectal cancer or glioblastoma (CR-CSC or GBM-CSC, respectively),
we’ve found that the wild-type MET oncogene -the HGF receptor- confers primary resistance to standard therapies. In CR-CSC, MET counteracts the proliferative blockade imposed by EGFR inhibitors. Thus, in mouse
models of CR-CSC xenografting in the presence of human HGF, we’ve shown that concomitant inhibition of
EGFR and MET results in a greater and more durable tumor regression as compared with EGFR inhibition alone.
In GBM we’ve shown that MET is a functional marker of a specific subset of CSC, and activates a signalling
pathway that protects CSC from DNA damage and cell death induced by ionizing radiation. Consistently, MET
inhibition sensitizes GBM-CSC to radiotherapy in vitro and in vivo, leading to enhanced regression of tumors
Cultures enriched in cancer stem cells
obtained by xenografting GBM-CSC, prolonged mouse survival, and eradication of the GBM-CSC subpopulation.
Conclusions and perspectives:
The MET oncogene is crucial to sustain CSC viability and long-term propagation. In metastatic CRC and
GBM, we’ve provided preclinical evidence that MET targeting impairs CSC properties, and increases the effectiveness of current therapies aimed at affecting cell proliferation (e.g. EGFR inhibitors) or DNA integri-
Selected references
ty and cell survival (e.g. radiotherapy). These results can instruct clinical trials that associate MET inhibi-
Boccaccio C, Luraghi P, Comoglio PM. MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal
cancer stem cells. Cancer Res. 2014. 74:3647-51
tors with standard therapeutic protocols. Current work is aimed at identifing (i) the genetic and molecular
context that modulates the CSC response to MET inhibitors; (ii) the intratumoral CSC genetic and phenotypic heterogeneity, which must be recognized to refine the targeted treatment of each individual tumor.
Luraghi P, et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.
Cancer Res. 2014, 74:1857-69
Boccaccio C and Comoglio PM. The MET oncogene in glioblastoma stem cells: implications as a diagnostic marker
and a therapeutic target. Cancer Res. 2013, 73:3193-9.
De Bacco F, et al. The MET oncogene is a functional marker of a glioblastoma stem cell subtype. Cancer Res. 2012, 72: 4537-50
36 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 37
Candiolo Cancer Institute
Research topic:
Integrative genomics of cancer progression
and resistance to treatments
Enzo Medico MD, PhD
Laboratory of Oncogenomics
Associate Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933234
Fax. +39.011.9933225
The integration of molecular profiles and clinical information enables accurate determination of cancer aggressiveness and response to treatment, to individualize therapeutic approaches (precision medicine)
Team
Claudio Isella, Consalvo Petti, Gabriele Picco, Sara Erika Bellomo, Andrea Mignone
Biographical Sketch:
Integrative genomics of cancer progression and resistance to treatment.
Enzo Medico graduated in Medicine at the University of Torino in 1989 and got a PhD in Cell and Developmental
Background: Cancer progression involves accumulation by neoplastic cells of multiple molecular alterations
Biology in 1994, University “La Sapienza” of Rome. Since 2005 he is associate professor at the University of
conferring metastatic ability and resistance to treatment. Over the last years, large international consortia have
Torino. Dr Medico has a long-standing activity in the field of tyrosine kinase receptor signaling and genomics.
been delivering multi-layer molecular data (gene mutation, expression, copy number, etc.) for large series of
In particular, he has worked on the MET family of tyrosine kinase receptors, showing their role in the control of
clinically annotated tumor samples. Integrative analysis of such data has two main outcomes: (i) improved pa-
epithelial morphogenesis and invasive growth. Since 1998, Dr. Medico has re-directed his research in the field
tient stratification into subgroups with different prognosis and treatment sensitivity (“molecular subtyping”); (ii)
of functional genomics. In collaboration with the Fred Hutchinson Cancer Research Center, Seattle, he develo-
identification of patient-specific alterations that at the same time drive the neoplastic phenotype and provide
ped a “gene trapping” approach for genome-wide exploration of transcriptional regulation. Dr. Medico has been
an effective therapeutic target (“precision medicine”).
among the first Italian users of DNA microarrays technology, exploiting it since 1999 to study alterations in
transcriptional regulation, gene expression and function associated with cancer aggressiveness and resistance
Research achievements:
to treatment. In 2004 he became director of the Laboratory of Oncogenomics at the Candiolo Cancer Institute.
Over the last two years, the Laboratory of Oncogenomics has been focusing on colorectal cancer (CRC) and on
Over the last ten years, he has been managing and coordinating functional oncogenomics projects led by the
the generation and analysis of multi-layer molecular and pharmacological data on large sets of CRC samples,
Institute and funded, among others, by the Italian Government, by AIRC and by the European Commission.
patient-derived xenografts (PDXs) and cell lines. The main achievements are summarized here: (i) identification
of MACC1 mRNA levels as a prognostic indicator for liver-metastatic colorectal cancer; (ii) species-specific
genomics of CRC PDXs to distinguish the stromal transcriptome, contributed by murine cells, from the human
epithelial cancer transcriptome; (iii) identification of mixed mRNA/microRNA networks associated with CRC
subtypes; (iv) integrative pharmacogenomic profiling of a large collection of CRC cell lines (n=151), validating
molecular subtypes and providing new actionable expression outliers in specific cases; (v) identification of
RAF1 and BRAF truncations as mediators of resistance to RTK-targeted therapy ; (vi) development of “Genome
Cruzer”, a 3D-interactive platform for visualization and analysis of large cancer datasets with multiple molecular and clinical layers (www.genomecruzer.com); (vii) development of a procedure for high efficiency in vivo
transduction of PDXs with lentiviral vectors; (viii) identification of NEDD8 pathway inhibition as an effective
therapeutic option in KRAS- and BRAF-mutant CRC, and in vivo validation of a molecular response predictor.
Sharing the genomic expertise of the Laboratory with other groups inside and outside the Institute also led to
publication of several collaborative works.
Conclusions and perspectives:
The Laboratory will continue exploiting integrative genomics for better molecular stratification and for highlighting actionable therapeutic targets in CRC and other neoplastic diseases.
Selected references
Zecchin D, et al. BRAF V600E is a determinant of sensitivity to proteasome inhibitors. Mol Cancer Ther. 2013,
12:2950-61.
Isella C, Renzulli T, Corà D, Medico E. Mulcom: a multiple comparison statistical test for microarray data in
Bioconductor. BMC Bioinformatics. 2011, 12:382.
Misale S et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
Nature. 2012,486:532-6.
38 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 39
Candiolo Cancer Institute
Research topic:
Pharmacogenomics of colorectal cancer
Federica Di Nicolantonio PhD
Laboratory of Cancer Epigenetics
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933827
Fax. +39.011.9933225
The knowledge of specific molecular alterations in the tumor DNA repair pathway could define a novel context of
susceptibility for alkylating agents
Team
Ludovic Barault, Daniele Oddo
Biographical Sketch:
Predictive and prognostic role of specific or global epigenetic variants in cancer.
Federica Di Nicolantonio holds a PharmD degree (1999) and gained a PhD (Medicine) from University College
London, UK, in 2004. Her research focuses on the molecular mechanisms underlying cancer cells’ response
Background:
to antineoplastic drugs. In her previous work she has given a significant contribution to discovering and esta-
Epigenetic regulation is key to many stages of tumor development. Epigenetic changes such as global DNA
blishing several cancer pharmacogenomic relationships. She identified KRAS mutations and KRAS amplifi-
hypomethylation and promoter-specific hypermethylation are found in early-stage tumors, making ideal mar-
cation as biomarkers of resistance to the mTOR inhibitor everolimus (Di Nicolantonio F et al., J Clin Invest.
kers for tumor detection and monitoring disease burden. Epigenetic mechanisms regulate the plasticity of
2010 20(8):2858-66) and EGFR monoclonal antibodies (Valtorta E et al., Int J Cancer. 2013;133(5):1259-65),
tumor cells and may underlie some forms of drug resistance. Most epigenetic modifications may be reversible
respectively. She is the leading author of a highly cited manuscript that first described BRAF mutations as a
(and/or preventable) by pharmacological targeting of DNA methylation and histone acetylation and methyla-
biomarker of adverse prognosis and of resistance to EGFR targeted therapies in colorectal cancer patients (Di
tion. This laboratory was set up in 2012 to study the predictive and prognostic role of specific or global epige-
Nicolantonio F et al., J Clin Oncol. 2008;26(35):5705-12). This paper has received over 1000 citations so far
netic variants in cancer. On one hand we aim to assess whether and how epigenetic mechanisms cause drug
and lead to the special mention in the 2011 Lorini Prize. Dr Di Nicolantonio contributed as a co-first author to
resistance in colorectal cancer (CRC); on the other, we aim to develop non-invasive methods to monitor changes
the discovery that lack of efficacy of BRAF inhibitors could be mediated by EGFR, hence leading to the design
in DNA methylation in cancer patients undergoing therapy.
of clinical studies aimed at testing combinations of EGFR and BRAF inhibitors (Prahallad A*, Sun C*, Huang
S*, Di Nicolantonio F* et al.,Nature. 2012; 483(7387):100-3). This preclinical work has provided the rationale
Research achievements:
for testing BRAF and EGFR inhibitors in colorectal cancer patients. Dr Di Nicolantonio has co-authored over
We have implemented a new assay to quantitate methylation both in tumor and plasma samples based on an
60 publications in peer-reviewed journals (H-index=24), three patents, and has given several invited lectures at
ultra-sensitive two-step digital PCR (ddPCR) technique followed by detection via fluorocytometer. As a test case,
both national and international meetings.
we focused on methylation of the O6-Methyl-Guanine-Methyl-Transferase (MGMT) gene. MGMT silencing by
promoter methylation is commonly found in multiple cancers, and is prognostic and predictive of response to
alkylating agents in glioblastoma (GBM). However, its value in malignancies other than brain tumors remains
highly controversial. Methylated status of MGMT as assessed by ddPCR better defined a GBM patient subset
with longer overall survival (p<0.001) compared to other techniques (including methylation specific PCR or
pyrosequencing). In CRC patients, MGMT methylated status by ddPCR in either tissue or circulating tumor
DNA was associated with better disease control rate with dacarbazine, as well as significant improved median
progression-free survival (p=0.006).
Conclusions and perspectives:
In conclusion, our ddPCR technology outperformed commonly used methods for detecting MGMT methylation
and allowed tumor molecular characterization from plasma. In the future, we wish to apply the same technology to other genes to track tumor burden in CRC as well as to detect mechanisms of drug resistance in BRAF
Selected references
mutant CRC patients. I have previously shown that preclinical models of BRAF mutant CRC are resistant to
Zecchin D, et al. BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors. Mol Cancer Ther. 2013, 12:2950-61.
BRAF/MEK targeted agents or EGFR inhibitors in monotherapy, but are sensitive to their combination. These
combo regimens are being tested in 7 clinical trials. We have generated BRAF mutant CRC cells with acquired
resistance to combinations of BRAF/MEK and EGFR inhibitors. These cells will undergo functional screening in
the laboratory of Prof R. Bernards (NKI) by exploiting a ‘chromatin regulator’ library of shRNAs targeting 661
genes to unveil epigenetic mechanisms of drug resistance.
Valtorta E, et al. KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy.
Int J Cancer. 2013, 133:1259-65.
Prahallad A, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.
Nature. 2012, 483:100-3.
Di Nicolantonio F, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines
their response to everolimus. J Clin Invest. 2010, 120:2858-66
40 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 41
Candiolo Cancer Institute
Research topic:
Personalized therapy and non-invasive molecular diagnostics of
colorectal cancer
Alberto Bardelli PhD
Laboratory of Molecular Oncology
Associate Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933235
Fax. +39.011.9933225
To define the genetic and molecular characteristics of patients in order to lead and check the treatment
of colorectal cancer
Team
Sabrina Arena, Giovanni Crisafulli, Giovanni Germano, Sebastian Hobor, Simona Lamba, Luca Lazzari, Sandra
Misale, Mariangela Russo, Beth Van Emburgh, Giulia Siravegna, Carlotta Cancelliere, Benedetta Mussolin,
Luca Novara, Giuseppe Rospo
Biographical Sketch:
Clonal evolution and drug resistance: from cancer avatars to liquid biopsies.
Prof. Bardelli received a PhD in Molecular Biology from the UCL (University College London, UK). As a post
doc at the Johns Hopkins University (Baltimore, USA, supervisor Dr Bert Vogelstein) he developed the first
Background:
comprehensive mutational profile of kinases (Bardelli et al Science 2003). As an independent investigator Prof.
A central paradigm of modern oncology is that tumor-specific molecular alterations underlie ‘functional’ depen-
Bardelli has then translated these findings into clinical practice (Moroni et al., Lancet Oncology 2005; Di Nico-
dencies that can be therapeutically exploited. Remarkable results have been obtained by applying this paradigm
lantonio et al., JCO 2008). Recently, Prof. Bardelli’s work has defined mechanisms of acquired resistance to anti
in the clinic, and several targeted drugs have been approved to treat, among others, melanomas, lung and co-
EGFR therapies in colorectal cancer patients thus providing insights into new therapies aimed at overcoming re-
lorectal cancers. Unfortunately even when applied to the ‘right’ patient, that is when they are tailored to a mo-
sistance (Misale et al., Nature 2012; Bardelli et al., Cancer Discovery 2014). These studies involve an innovative
lecularly defined subset of tumors, the efficacy of targeted drugs is transient. Virtually all patients undergoing
methodology - named liquid biopsy - which allows the use of circulating tumor DNA to monitor patient’s respon-
treatment with targeted agents eventually acquire pharmacological resistance (‘secondary’ or ‘acquired’) and
se using a blood draw (Misale et al., Science translational Medicine 2014). The H factor of Prof Bardelli is 58.
undergo tumor relapse or progression. Arguably, the rapid and apparently unavoidable emergence of resistan-
In 2014 he has been listed in the Thomson Reuters List of Highly Cited Researchers (http://highlycited.com/).
ce is the major limitation to further progress in the application of targeted therapies in oncology. How can we
overcome the near-certainty of disease recurrence following treatment with targeted agents?
Research achievements:
We have used colorectal cancer (CRC) as a model system to test the hypothesis that the emergence of drug resistance can be controlled. To this goal, we studied how clonal evolution impacts the development of resistance in
patients’ avatars (cell lines and tumor xenografts). In parallel, we analysed clonal evolution dynamics and drug
resistance in the blood of patients (liquid biopsies) who receive targeted therapies. Our results indicate that
acquired resistance is -for the most part- a ‘fait accompli’. Mathematical models based on our data suggest that
each (traceable) metastatic lesion contains hundreds of cells with mutations to virtually any targeted agents.
According to this model, the time to relapse is simply the interval required for mutant or otherwise altered subclones to re-populate the lesion. On the positive side, we found that resistance can be prevented when drug
combinations are rationally used.
Conclusions and perspectives:
The awareness that in nearly all patients targeted drugs are only transiently effective due to the rapid emergence of resistance poses a formidable challenge. Although the overall picture is looming, our data and the
concepts they underlie offer several opportunities for intervention. Genetic tracking of cancer cell populations
can be used to study how the development of resistance can be restrained in vitro and in vivo. Furthermore,
Selected references
liquid biopsies can be exploited to monitor clonal evolution and to intercept the emergence of resistant clones
Sun C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014, 508:118-22
non-invasively in patients. When applied together cancer avatars and liquid biopsies may identify, monitor and
potentially overcome resistance to targeted therapies.
Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014, 32:579-86
Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood.
Nat Rev Clin Oncol. 2013,10:472-84.
Misale S et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
Nature. 2012, 486:532-6
42 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 43
Candiolo Cancer Institute
Research topic:
Antibody gene transfer for ‘active’ targeted cancer immunotherapy
Elisa Vigna PhD
Laboratory of Gene Transfer
Research Associate
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933228
Fax. +39.011.9933225
Development of novel therapeutic strategies to generate, produce and deliver monoclonal anti-cancer antibodies
Team
Simona Cignetto, Cristina Chiriaco, Lara Fontani
Biographical Sketch:
Antibody gene transfer for targeted cancer immunotherapy.
Elisa Vigna started her research experience in the field of growth control in normal and neoplastic cells. She was involved in the identification of HGF/SF as the Met ligand (Oncogene, 1991; 6:501-04; EMBO J., 1991; 10:2867-78.)
Background:
and in the characterization of the biological activation of HGF by urokinase (EMBO J., 1992; 11:4825-33; J Biol Chem,
Clinical evidence indicates that the MET oncogene plays a role in progression of cancer toward metastasis and/or
1995; 270:603-11). She studied the role of the Met juxtamembrane domain in the regulation of Met activity.
resistance to targeted therapies. While mutations are rare, the common mechanism of MET activation is overexpres-
(Vigna et al., Oncogene; 18: 4275-81). In the gene therapy field she acquired experience joining Prof. Naldini,
sion, either by gene amplification (‘addiction’) or transcriptional activation (‘expedience’). In both instances ligand-
who conceived and developed the Lentiviral Vectors. She performed pionieristic ‘vectorology’ studies optimizing
independent kinase activation plays the major role in sustaining the transformed phenotype. Currently available MET
lentiviral vectors for multiple gene transfer and exogenously regulated expression (Vigna et al., Mol. Therapy,
antibodies are directed against the receptor binding site, behaving essentially as a ligand (HGF) antagonist, and are
2002; 5:252-56; Vigna et al., Mol. Therapy, 2005; 11:763-75; Nature Biotech, 2005, 23:108-16). She characte-
ineffective in ligand-independent activation.
rized the anti-Met antibody DN30 and generated its monovalent non-agonistic counterpart. She provided proof
of concept for either conventional or ‘gene transfer based’ protocols for DN30 application (Vigna et al., Cancer
Research achievements:
Res, 2008; 68:9176-83; J Biol Chem, 2010; 285:36149-57; Vigna et al., J Mol Med 2014; 92:65-76).
The monovalent chimeric MV-DN30 antibody, delivered as a purified protein, binds the fourth IPT extracellular domain
and induces proteolytic cleavage of MET, dramatically inhibiting downstream signaling pathways, in both the absence
or presence of ligand. As an inventive approach, Mv-DN30 was delivered by ‘gene therapy’ driven by a second generation bidirectional lentiviral vector. In vitro, the antibody displayed a strong inhibition of ligand independent invasive
growth of MET ‘addicted’ cancer lines, and –notably- of primary cells from a MET amplified gastric ca. patient. In vivo
the antibody strongly impaired the growth of a panel of MET ‘addicted’ human cancer lines, xenotransplanted in nude
mice lacking HGF. In patient-derived RAS wt colorectal cancer xenografts, MET amplification was found to correlate with
resistance to anti EGFR therapy. By the gene therapy approach, direct Mv-DN30 gene transfer in nude mice, intra-tumor
or systemic, was followed by a therapeutic response of MET addicted human glioblastomas and lung carcinomas.
Conclusions and perspectives:
To further develop the MV-DN30 antibody as a strong candidate for targeting tumors sustained by ligand-independent
MET oncogenic activation, resulting from MET amplification or mutations, and for overcoming resistance to anti-EGFR
therapies. These studies will also provide proof of concept for a gene transfer immunotherapy strategy and encourage
clinical studies with Mv-DN30.
Selected references
Vigna E, et al. Targeted therapy by gene transfer of a monovalent antibody fragment against the met oncogenic
receptor. J Mol Med (Berl). 2014, 92:65-76
Olwill SA, et al. A highly potent and specific met therapeutic protein antagonist with both ligand-dependent and
ligand-independent activity. Mol Cancer Ther. 2013, 12:2459-71
Basilico C, et al. TIVANTINIB (ARQ197) Displays cytotoxic activity that is independent of its ability to bind MET.
Clinical Cancer Research 2013, 19:2381-92
44 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 45
Candiolo Cancer Institute
Research topic:
Mechanisms of resistance to tyrosine kinase receptor inhibitors
Silvia Giordano MD, PhD
Laboratory of Molecular Biology
Full Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933233
Fax. +39.011.9933225
Design of strategies bypassing resistance to targeted therapies
Team
Simona Corso, Elena Ghiso, Valentina Martin, Silvia Menegon, Cristina Migliore, Annalisa Petrelli,
Maria Apicella, Marilisa Cargnelutti, Elena Morando
Biographical Sketch:
Molecular mechanisms responsible for response/lack of response to molecular therapies targeting receptor
Silvia Giordano has a long experience in the field of research on tyrosine kinase receptors and related onco-
tyrosine kinases.
genes. She has focused her research on the study of the tyrosine kinase receptor encoded by the MET gene.
She identified this receptor (Nature. 1989; 339:155-6.) and contributed to the understanding of the signal
Background:
transduction mechanisms and of the biological role in physiological as well as in pathological conditions.
The goal of delivering the right drug to the right cancer patient requires understanding how genomic alterations
In particular, she has critically contributed to the understanding of the mechanisms controlling MET down-
are linked to drug response. Hence, the clinical efficacy of targeted therapy depends on: (i) the validation of the
regulation (Nature 416: 187-190, 2002) and HGF-independent activation (Nature Cell Biol. 9, 720-724, 2002).
true biological relevance of putative targets in the context of a specific tumor type; (ii) the context-specific iden-
Moreover, she showed that cancer cells may be dependent (“addicted”) on the constitutive activation of this
tification of the active drug(s) and of additional molecular alterations affecting the responsiveness to treatment.
oncogene (Oncogene; 27:684-93, 2008). Recently, she has been deeply involved in the study of the mechanisms of resistance to targeted therapies (Cancer Res; 70:7580-90, 2010 ; Cancer Discovery, 3:658-73, 2013).
Research achievements:
She has also performed studies of the role of microRNAs in cancer progression (Cancer Res., 68:10128-36,
We have studied the mechanisms responsible for response/lack of response to molecular therapies targeting
2008; Clin. Cancer Res., 18:737-47, 2012; Hepatology. 59: 228-41, 2014). On the translational front she has
receptor tyrosine kinases (RTK). In particular we have shown that: (i) the amplification of the MET proto-on-
identified a MET monoclonal antibody (DN30) able to impair Met activation and tumorigenicity. (Proc Natl Acad
cogene is responsible for de novo and acquired resistance to anti-EGFR therapy in colorectal carcinomas. (ii)
Sci U S A. 103:5090-5, 2006). Silvia Giordano is author of more than 110 papers, published in peer-reviewed
Resistance of MET-addicted cells to treatment with a MET-antibody (MV-DN30) can be sustained by an increase
journals. In January 2014 she was elected as President of the Italian Society of Cancer Research.
of MET gene copies and overexpression of the MET receptor. Notably, antibody-resistant cells became ‘drugdependent’ since the removal of MV-DN30 led them to death due to excess of signal. Finally, MV-DN30 and MET
kinase inhibitors (TKIs) showed a synergistic effect on tumor cells. These findings suggest that a discontinuous,
combined treatment with antibodies and TKIs may increase the clinical response and bypass resistance to antiMET targeted therapies. (iii) Activation of members of the RAS family can confer resistance to inhibitors of
the ROS1 RTK. This has important clinical implications as: (a) RAS alterations in ROS1+ tumors are negative
predictors of efficacy for targeted drugs and (b) this resistance is unlikely to be overcome by the use of more
potent ROS1 targeting drugs. (iv) By exploiting a large colony of gastric PDX (Patient-derived-xenopatients),
we are generating a study population that will be profiled for biomarker assessment and prospectively tested
with targeted agents. This approach combines the flexibility of preclinical analysis with the informative value
of population-based studies. Starting by targeting HER2, half of gastric cancer patients could be potentially
treated with RTK-directed therapies against ‘druggable’ targets. Making use of PDXs, we will validate known
potential actionable targets, performing `clinical’ trials in mice with matching targeted drugs. To assure the
feasibility of the project, in the last year we: (i) established a network of 15 centers for sample collection; (ii)
optimized tumor engraftment in NOD-SCID mice. So far 46 samples have been implanted with an engraftment-
Selected references
learning curve going from the original 30 % to the current >60%; (iii) identified patients bearing HER2, EGFR,
Perra A et al. YAP activation is an early event and a potential therapeutic target in liver cancer development.
J Hepatol. 2014, 61:1088-96.
FGFR2, MET and KRAS amplification and generated the corresponding PDX; (iv) performed a pilot study, from
a MET amplified gastric cancer.
Conclusions and perspectives:
Resistance is, at present, the major limit of the efficacy of target therapies. Deciphering the mechanisms sustaining resistance to targeted therapies could guide the design of new clinical trials based on combinatorial
therapies and it might help to overcome, or possibly prevent, resistance onset.
46 | From Molecular Biology to “Precision Medicine”
Petrelli A, Perra A, Corà D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM, Giordano S,
Columbano A. Mirna/gene profiling unveils early molecular changes and nrf2 activation in a rat model recapitulating
human hcc. Hepatology. 2014, 59:228-41
Corso S., Giordano S. Cell-autonomous and non-cell-autonomous mechanisms of hgf/met-driven resistance to
targeted therapies: from basic research to a clinical perspective. Cancer Discov. 2013,3:978-92
From Molecular Biology to “Precision Medicine” | 47
Candiolo Cancer Institute
Research topic:
Experimental cancer immunotherapy with
Cytokine-induced killer cells
Dario Sangiolo MD
Unit of Experimental Cell Therapy
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933503
Fax. +39.011.9933290
Adoptive immunotherapy against solid tumors
Team
Loretta Gammaitoni, Lidia Giraudo Diego, Giulia Mesiano, Valeria Leuci
Biographical Sketch:
Immunotherapy with Cytokine-Induced Killer (CIK) cells for the treatment of solid tumors refractory to conven-
Dario Sangiolo is a physician scientist with research interest in the field of transplant immunology developed
tional treatments.
at the Fred Hutchinson Cancer Research Center (Seattle, WA). He contributed to the development and characterization of preclinical models based on Cytokine-Induced Killer (CIK) cells (Int Immunol. 2008; J Immunother.
Background:
2012). In preclinical studies he demonstrated the activity of CIK cells against melanoma and sarcomas (Clin
Adoptive immunotherapy holds promise for the treatment of solid tumors. Disease relapse and drug-resistance
Cancer Res. 2013; Cancer Res. 2014 ). He explored strategies to genetically engineer T lymphocytes to enhance
are sustained by a subset of putative cancer stem cells (CSC), poorly responsive to conventional treatments.
antitumor activities and decrease the risk of GVHD across HLA barriers (Hum Gene Ther. 2009; Gene Ther.
Immunotherapy is a promising approach capable of targeting putative CSC. Our group has focused over the last
2007). In the field of clinical research he investigated the efficacy and toxicity of Hematopoietic Cell Transplant
years on a subset of T lymphocytes known as Cytokine-induced Killer (CIK) cells. CIK cells are ex vivo expanded
in hematologic and solid tumors (Biol Blood Marrow Transplant. 2010; Blood. 2006 May).
T lymphocytes generated from circulating mononuclear cells, endowed with MHC-independent antitumor activity. The aim of our research is to explore adoptive immunotherapy with CIK cells for sarcomas and melanoma.
Research achievements:
We demontrated that immunotherapy with CIK cells is active against autologous sarcomas and melanoma,
TCR
CD3
including putative CSC. Our main findings are summarized as follows. (i) Generation of CIK cells: clinically
CD56
relevant rates of CIK cells were successfully expanded from patients with sarcomas and melanoma; (ii) tumor
LFA-1
killing activity: patient-derived CIK cells were highly active against autologous sarcomas and melanoma in vitro
ULBPs
tumor cell
CD155
DNAM-1
and in vivo; (iii) activity against CSC: we developed a lentiviral CSC-detector capable of visualizing putative CSC
CIK cell
based on their ability to re-activate stem gene Oct4. Immunotherapy with CIK cells efficiently killed autologous
NKG2D MICA/B
CSC in sarcoma and melanoma models, in vitro and in vivo.
Conclusions and perspectives:
Adoptive Immunotherapy with CIK cells
Adoptive immunotherapy with CIK cells is potentially active against solid tumors and capable of eradicating
CSC. We plan to explore synergism of immunotherapy with molecular targeted approaches and focus on counteracting drug resistance and disease relapse.
Selected references
Grignani et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after
standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncology. 2015, 16:98-107
Sangiolo D. et al. Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas. Cancer Research. 2014, 74:119-29
Gammaitoni et al. Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including
cells with stemness features. Clinical Cancer Research. 2013, 19:4347-58
Todorovic et al. Ex vivo allogeneic stimulation significantly improves expansion of cytokine-induced killer cells without
increasing their alloreactivity across HLA barriers J Immunother. 2012, 35:579-86
48 | From Molecular Biology to “Precision Medicine”
From Molecular Biology to “Precision Medicine” | 49
Candiolo Cancer Institute
Research topic:
Research Topic 3
Investigational Clinical Oncology
Over the past few years, the improved knowledge on the biological, genetic and molecular heterogeneity of
tumors, together with the development of pharmacological technologies, has allowed the identification of
molecular targets for novel therapeutic strategies. This fast process has led to the overall reconsideration of
classical approaches to clinical oncology, traditionally oriented toward design of cancer treatments irrespective
of the biological and genetic peculiarities that can make each tumor a pathology on its own. The identification
of patients likely to respond to specific treatments according to the presence of relevant molecular targets
(personalized medicine) and based on the expression of potential markers of sensitivity or resistance, needs
clinical studies that result from a constant and productive interaction among the professionals with a significant
background in the various disciplines.The goal of the “Investigational Clinical Oncology” team is to increase
the therapeutic index of molecular targeted drugs, by the identification and clinical validation of biomarkers of
sensitivity/resistance. This goal is pursued through the development of research programs aimed at designing
hypothesis-driven clinical trials that directly derive from the Institute’s biological, genetic and molecular research.
In order for these tasks to be implemented, an ad-hoc organizational structure favours the interchange and the
synergy among preclinical researchers, oncologists and pharmaceutical companies – which are the potential
providers of new drugs for clinical trials. Another of INCO’s goals will be the promotion of a clinical research
culture based on the knowledge of molecular biology and tumor genetics, and particularly of the mechanisms
of sensitivity or resistance to molecular targeted drugs. This organization is instrumental to the referral of
patients for admission into top-priority clinical trials.
Research Topic 3 is focused on:
3.0 Rational design of clinical trials for targeted drugs.
AGNOSTOS is a precision medicine project aimed at addressing both clinical and translational needs of CUP, a
heterogeneous clinical syndrome represented by metastatic tumors that are first-time diagnosed in the absence
of a clinically detectable primary lesion. Three protocols are embedded in the project: AGNOSTOS Profiling, a
non-treatment protocol to collect biological specimens from CUP patients for translational purposes; AGNOSTOS
Trial, a multicenter, randomized phase 2 trial with a ‘Pick the Winner’ design in treatment-naïve CUP patients;
AGNOSTOS 2, an observational therapeutic protocol for previously chemotherapy treated patients aimed at selecting patients for target therapy according to the molecular profile of their CUP tumors.
50 | Investigational Clinical Oncology
Investigational Clinical Oncology | 51
HERACLES and ARES: trials for the ‘Precision Medicine’ of Cancer
Silvia Marsoni MD
Unit of Clinical Trials
E-mail: [email protected]
Phone. +39.011.9933926
Fax. +39.011.9621525
Shaping the clinical validation path of new putative targets found in the Institute’s preclinical programs
Team
Antonella Balsamo, Cosimo Martino, Marilì Vitiello, Mario Spione
Biographical Sketch:
Design, implementation and conduction of ‘hypothesis-driven’, precision medicine trials based on the transla-
Silvia Marsoni has a distinguished career as a clinical trial methodologist, which started in the ’80 at the NCI-
tional discoveries of the FPO-IRCC research laboratories
USA. Since then, she has focused her research efforts on the rationalization of oncology trials. In the nineties at
the Mario Negri Institute she founded her first clinical network and designed pivotal phase 3 trials establishing
Background:
the standard of care in the adjuvant setting of colon cancer . Currently, she still designs standard-defining trials
Precision medicine brings a new set of challenges to clinical application. To hasten the adoption of new thera-
for genotype selected populations. In 2000 she founded SENDO, a non-profit organization for the early deve-
pies we need to achieve a deeper molecular understanding of cancers and reliably translate results from repre-
lopment of new cancer drugs in Italy and Spain. SENDO, firstly in Italy, developed targeted drugs in biomarker
sentative preclinical models into clinical trials enriched with suitably identified patients.
enriched populations . While there she also developed trabectidin in ovarian cancer . Since 2011 she directs
the Clinical Trials Unit, and has built the clinical platform for genomic-driven trials serving the translational
Research achievements:
labs of the Institute. The first of these trials, HERACLES ,is targeting HER2 in colorectal cancer with promising
At Candiolo we have started to confront precision medicine hurdles by creating a clinical platform integrating,
preliminary results. In the last 20 years she has authored more than 80 clinical research papers published in
under the same virtual roof, the efforts of surgeons, pathologists, radiologists, and medical oncologists from
peer-reviewed Journals.
the IRCC clinical network (25 centers around Italy), in order to assemble the timely collection of high quality,
clinically annotated biological samples at meaningful time points, to feed research projects and precision medicine trials. Five translational protocols are now feeding the translational Labs of the Institute (PROFILING,
AGNOSTOS-Profiling, GEA, FUNNEL and CORNUCOPIA). Together with the translational scientists, we are also
building a “cancer knowledge network” to store the resulting molecular and medical data in digital form and
to deliver them, in comprehensible ways, to scientists, clinicians, and patients (Projects LAS and PROBUS).
Three hypothesis driven clinical trials have been designed and implemented (HERACLES and ARES in colorectal cancer, AGNOSTOS in cancer of unknown origin). HERACLES has been the the Institute first precision trial
designed upon the discovery, based on PDX studies, that HER2 amplification in metastatic colorectal cancer
(mCRC) associates with resistance to anti-EGFR therapy, and predicts response to the combination of lapatinib
and trastuzumab for a dual blockade of the HER2 pathway. Accordingly, we conducted a proof-of-concept trial
testing the combination in HER2 amplified mCRC patients failing standard therapies. The trial has proven the
efficacy of the combination with 8 long lasting responders out of 23 patients treated, proving HER2 as the first
bona fide actionable target in mCRC. Genotype/response correlation has shown that only patients with truly
‘HER2 addicted’ tumors benefit from this therapy. The tumor genomic landscape of non-responders and relapsing cases is under scrutiny to define the determinants of primary and secondary resistance.
Conclusions and perspectives:
Selected references
In the next year we will focus on addressing the obstacles encountered in HERACLES: unexplained primary drug
Bergmann L, et al. Actual developments in European regulatory and health technology assessment of new cancer
drugs: what does this mean for oncology in Europe? Ann Oncol. 2014, 25:303-6.
resistance, inadequacy of current criteria for monitoring tumor response and recurrence, limited knowledge of
genomic heterogeneity of mCRC. We will also extend the dynamic research infrastructure which we have created
for mCRC to gastric cancer and cancers of unknown origin. Two new resource-dense, hypothesis-driven trials
deriving their rationale from the results of the Institute’s translational labs, will be embedded and nurtured by
this infrastructure.
52 | Investigational Clinical Oncology
Garassino MC, et al. TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced
non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013,
14:981-8.
De Marinis F, et al. A phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in pretreated patients
with small-cell lung cancer. J Thorac Oncol. 2013, 8:1091-4
Investigational Clinical Oncology | 53
Candiolo Cancer Institute
Research topic:
HERLAP:
Personalizing HER2-positive breast cancer treatment
Filippo Montemurro MD
Unit for Investigation and Therapy of Breast Cancer
E-mail: [email protected]
Phone. +39.011.9933621
Fax. +39.011.9933275
To optimize HER2 molecular target therapies to avoid, if possible, standard cytotoxic chemotherapy in this subgroup
of patients with breast cancer
Team
Elena Geuna, Andrea Milani, Valentina Rossi, Annamaria Nuzzo
Biographical Sketch:
Molecular biomarkers of sensitivity for HER2-target therapy.
Dr. Filippo Montemurro is the Director of the Investigative Clinical Oncology Unit (INCO) at the Candiolo Cancer
Institute - FPO IRCCS. This recently created Unit is at the interface between basic, translational and clinical
Background:
research and is strongly committed to designing clinical trials of cancer precision medicine.
Amplification of the human epidermal growth factor receptor 2 (HER2) gene, which results in overexpression of
During his fellowship and his professional career, Dr. Montemurro has focused on breast cancer and biologically
its transmembrane tyrosine-kinase receptor product, is found in about 15% of breast cancers. This abnormality
targeted therapies for the HER2-positive subset, where he has acquired competence and international visibility.
drives an aggressive clinical phenotype. HER2-treatment in combination with chemotherapy has revolutionized
In particular, he has pioneered reductive approaches aimed at sparing chemotherapy to patients with HER2-
the outcome of patients with this otherwise rapidly fatal disease. While newer achievements in this field have
positive metastatic breast cancer whose disease shows molecular features of clinical addiction to the HER2
led to more and more complex forms of treatment (i.e. combination of multiple HER2-targeting agents with
oncogene.
chemotherapy) as standard of care, anecdotal experience and some clinical and experimental evidence indicate
Currently, he is Principal Investigator and steering committee member of a number of Phase II and III, multi-
that purely HER2-driven tumors may display exquisite sensitivity to simplified targeted therapies. Establishing
centric international Clinical Trials in breast cancer. Furthermore, in the context of the activities of the INCO
molecular markers of sensitivity, which is the main purpose of our project, would provide the basis for a more
unit, he co-chairs a special program in patients with metastatic Cancer of Unknown Primary origin (CUP),
rational utilization of the several anti-HER2 agents that are available and provide guidance for further refine-
which includes clinical and molecular investigations in this rare, but meaningful disease subset. Presently, Dr.
ments.
Montemurro has published 90 papers in international medical journals, a substantial proportion of which as
first, senior or corresponding author.
Research achievements:
We have shown that HER2-positive metastastic breast cancers respond differently to chemotherapy according
to hormone receptor co-expression. In particular, the now called “triple-positive” breast cancer (HER2, ER and/
or PgR positive) was found to be less responsive to chemotherapy and, possibly, better suited to free combinations of anti HER2-agents with endocrine therapy. This biological difference may also impact the scheduling and
duration of anti HER2-therapy in the adjuvant setting.
In a clinical trial that we conducted (HERLAP), we observed that tumors belonging to the HER2-enriched breast
cancer subtype and with a high HER2/p95 expression ratio are particularly sensitive to single agent anti HER2
therapy with trastuzumab or lapatinib. Patients whose tumor bears this biological profile may be suitable for
simplified treatments (i.e. sequential use of single-agent anti HER2-treatments with or without chemotherapy).
Conclusions and perspectives:
Results of the HERLAP trial suggest that a molecular profile can identify patients where the current standard of
combining chemotherapy with multiple HER2-targeting agents could represent an overtreatment and a potential
waste of resources. We are now seeking to validate our preliminary findings in the currently ongoing HERLAP
Selected references
(amendment 2) study. In this trial, 60 patients at their first diagnosis of HER2-positive, low-burden metastatic
Montemurro F, Scaltriti M: Biomarkers of drugs targeting HER-family receptors. J Pathol. 2014, 232:219-229
breast cancer receive trastuzumab and lapatinib without chemotherapy if the disease responds to biological
therapy. The translational research plan includes extensive evaluation of molecular markers that can identify
long-term responders, including but not limited to RNA expression profiles with the PAM50 test and whole genome analysis on tumor tissues and circulating DNA to establish mutated genes that could be related to outcome.
54 | Investigational Clinical Oncology
Montemurro F, et al.Potential markers of long-term benefit from single-agent trastuzumab or lapatinib in HER2positive metastatic breast cancer. Molecular Oncology. 2014, 8:20-26
Montemurro F, et al. Human epidermal growth factor receptor 2 (HER2)-positive and hormone-receptor positive
breast cancer: new insights into molecular interactions and clinical implications. Ann Oncol. 2013, 24:2715-2724
Montemurro F, et al. Hormone receptor expression and activity of trastuzumab with chemotherapy in HER2-positive
advanced breast cancer patients. Cancer 2012, 118:17-26
Investigational Clinical Oncology | 55
Candiolo Cancer Institute
Research topic:
AGNOSTOS: Target Therapy and Cancer of unknown primary (CUP)
Giulia Maria Stella, MD
Center for Metastasis of Unknown Primary Cancers (CUPs)
E-mail: [email protected]
Phone. +39.011.9933601
The project aims to build a genomic profile of CUPs, focusing on MET and selected oncogenes known to be frequently
mutated in cancer
Team
Paola Cassoni, Rebecca Senetta, Claudio Valizia, Patrizia Morbini
Biographical Sketch:
Cancer of Unknown Primary (CUP).
Dr Giulia Maria Stella graduated in Medicine and Surgery in 2001 at Pavia University Medical School. She got
the MD European Qualification in 2002. She obtained the specialization in Respiratory System Diseases in 2005
Background:
and completed a PhD in Pharmacological Sciences in 2005. In 2011 she obtained a Master degree in Molecu-
Cancer of unknown primary (CUP) is defined as metastatic cancer in the absence of a clinically detectable ana-
lar Oncology at Turin University Medical School. She is now working. As a clinical research assistant (Hospital
tomically defined primary tumor site, after an adequate diagnostic evaluation. This condition defines a highly
Medical staff) responsible for the pneumo-oncology DH at San Matteo Hospital Foundation in Pavia. She is a
malignant syndrome which accounts for up to 6% of the whole cancer population and - at to present - is still
lecturer in Respiratory System Diseases at Pavia University Medical School. Her research interest is focused
lacking appropriate therapies. While the majority of CUP related studies are focused on how best track down
on cancers of Unknown Primary origin (CUPs). Her work has documented the activation in this syndrome, by
the putative cancer of origin, the real enigma of this syndrome is related to its biological and genetic setting
somatic mutations, of the MET oncogene. She is now involved in both selecting and following CUP patients and
as supported by growing evidence suggesting that indeed the rationale for personalized targeted therapies is in
in analysing the genetic profile of these lesions, in a translational perspective. Her technical skills and Medical
the genomic alteration of cancer cells, rather than in the tissue of origin.
competences go from molecular and cellular biology, to biochemistry and bio informatics to clinical expertise
(invasive and Medical procedures required for thoracic cancer patient management). She is author of 24 peer-
Research achievements:
reviewed indexed papers. She is a member of the Editorial Board of Ars Pneumologica and Translational Lung
Given the highly aggressive metastatic phenotype of CUPs we have focused on the Met oncogene, a key player
Cancer Reseach. She has active collaborations with the University of Pennsylvania and with the Norwegian
of the ‘invasive growth program’, and have recently demonstrated a five-timess higher mutational incidence
University of Science and Technology.
(15% vs 3% of unselected cancer population) in a cohort of about 50 CUP patients.
Conclusions and perspectives:
The activity of the CUPs Center is part of AGNOSTOS, a larger program to optimize the diagnosis and the
treatment of CUP patients at our Institute. AGNOSTOS includes a comprehensive diagnostic algorithm and a
phase 2 trial in which patients, whose metastases harbor an ‘actionable’ molecular alteration including MET,
will be treated with the accordingly appropriate targeted drug. Treatment outcome will be monitored with both
traditional methods and BEAMing, a ‘liquid biopsy’ technique that uses the putative ‘actionable’ target as a
marker of therapeutic success. In addition, as part of this program, the tumor material of CUPs, which harbor
specific genetic lesions, will be implanted in immuno-compromised mice to establish human-mouse (Xenopatients) models of CUPs for preclinical studies.
Selected references
Stella GM, Luisetti M, Pozzi E, Comoglio PM. Oncogenes in non-small-cell lung cancer: emerging connections and
novel therapeutic dynamics. Lancet Respir Med. 2013, 1:251-61.
Stella GM, et al. MET mutations in cancers of unknown primary origin (CUPs). Hum Mutat. 2011, 32:44-50
Stella GM, Benvenuti S, Comoglio PM. Targeting the MET oncogene in cancer and metastases.
Expert Opin Investig Drugs. 2010, 19:1381-94
56 | Investigational Clinical Oncology
Investigational Clinical Oncology | 57
Candiolo Cancer Institute
Research topic:
Research Topic 4: Applied Clinical Research
HERACLES trial
Response to lapatinib and trastuzumab dual HER2 blockade in
HER2 amplified metastatic colorectal cancer patients refractory to
standard and anti-EGFR therapies
The AIRC 5x1000 Molecular Clinical Oncology Programme awarded to the Candiolo Cancer Institute aimed at tackling the limitations of current therapies in colorectal cancer to optimise patient selection and
increase response rates, two unmet medical needs that still await rational implementation. The Institute’s
translational research has been devoted to (i) identify novel drivers of de novo resistance to anti-EGFR
antibodies (including actionable molecules preferentially expressed by cancer stem cells) and challenge
such drivers as new therapeutic targets; (ii) investigate the mechanisms of acquired resistance; (iii) explore, at the preclinical and clinical level, new therapies for resistant colorectal cancer. To achieve these
objectives, the Institute’s research was centred around two innovative technological pillars: (i) genotype/
response correlations, mechanistic validation and investigational trials in ‘xenopatients’ (whereby animals
bearing molecularly annotated patient-derived xenografts are treated with rationally selected anti-cancer
compounds and monitored for response, relapse, tumour functional adaptation to therapy, and progression); (ii) the execution of ‘liquid biopsies’, a mutational analysis of cell-free circulating DNA, as a surrogate for non-invasive identification of cancer genetic variants. Using the xenopatient approach, the Institute
discovered that amplification of the HER2 oncogene, occurring in approximately 3% of colorectal cancer
patients, predicts resistance to anti-EGFR antibodies and response to a combination therapy with two
drugs co-targeting HER2. These preclinical data have inspired a multicentric trial to assess the efficacy of
this combination therapy in chemorefractory patients with HER2-amplified tumours resistant to anti-EGFR
antibodies (The HERACLES trial). The trial is about to be completed with outstanding results, with 34% of
patients experiencing tumour regression after having exhausted any available therapeutic option.
% of maximum tumor shrinkage in each patient
Dynamic representation of response in each patient
The ultimate task of the Institute is the development of clinical research integrated with health assistance, also
through nationally- and internationally-controlled clinical trials. With the introduction of molecular therapies,
it has been understood that a specific disease can have different characteristics that need different therapies.
Treatments are therefore oriented toward personalized therapy, which needs a very sophisticated molecular
diagnostics armamentarium that the Institute is able to provide. Ongoing clinical research integrates the Divisions,
the Laboratories and the Facilities, in order to allow synergy among different highly-specialized technologies
and complementary, diagnostic and therapeutic know-how. The research goal is the progress of science, but the
figure and the well-being of the patient are an absolute priority. The participation in the experimental protocols
is voluntary and is suggested to patients according to the biological and clinical characteristics of the disease.
The Ethics Committee of IRCCS-FPO guarantees that patients receive only treatments having solid scientific
bases and that they are monitored with the most serious attention. In compliance with the Declaration of
Helsinki, patient who do not wish to participate in a trial receives the best “standard” therapy.
Oncologists, surgeons, radiologists and radiotherapists cooperate with researchers to design clinical trials based
on molecular data, intended to verify and generate hypotheses. In order to make this cooperation productive,
the Institute manages a daily net of interactions involving formal aspects (seminars and meetings), training
(refresher courses and lessons) and operational efforts (contacts with pharmaceutical companies, regulatory
and management instruments).
Clinical Research is the last and most important haven to improve the assistance to cancer patients, to increase
their life expectancy and to provide them with the most appropriate, safe and effective therapeutic approach
according to the genetic characteristics of their own tumor. The controlled clinical Protocol is the final product
of the overall work of a multidisciplinary group composed of basic researchers, oncologists, surgeons,
pathologists, pharmacologists, radiologists and nuclear medicine doctors, biostatistics and bioinformatics
scientists, research healthcare assistants, data managers and legal experts. The main projects of the Applied
Clinical Research are listed below, followed by the table of Controlled Clinical Trials.
Research Topic 4 concerns:
4.1. Colorectal cancer: onset and progression
4.2. Development of new therapeutic strategies
4.3. New approaches to surgical oncology
4.4. Laboratory Medicine, Imaging and Radiotherapy
58 | Clinical Services
Clinical Services | 59
Stochastic modelling of colorectal tumorigenesis
Mauro Risio MD
Unit of Pathology
Medical Director
E-mail: [email protected]
Phone. +39.011.9933465
Identification of molecular and morphological markers of premalignant colon tumor lesions, to rationalize diagnostic
and therapeutic strategies
Team
Laura Casorzo, Carmine Dell’Aglio, Ivana Sarotto, Elena Frangipane, Alberto Pisacane
Biographical Sketch:
Aurora Kinase Gene A in the Early Steps of Colorectal Tumorigenesis
Mauro Risio has been director of the Division of Pathology at the Institute for Cancer Research and Treatment
since 1999. He was visiting Professor of the Department of Pathology at the Memorial Sloan-Kettering Cancer
Background:
Center, New York, in 1995. He was senior Scientist at the Strang Cancer Center, Cornell and Rockefeller Univer-
A crucial role for the Aurora Kinase A (AURKA) gene has been demonstrated in the advanced steps of colorectal
sity, New York 1996-2006.
tumor progression, likely through the promotion of a CIN phenotype, but little is known about its involvement in
Most of his scientific activity is related to the pathology of premalignant colorectal lesions. Mauro Risio has
the early steps of the adenoma-carcinoma sequence. Despite approximately 30% of colorectal cancers occur
supervised several international polycentric studies concerning the histological features of adenomas with inva-
by means of the serrated neoplasia pathway, no data are currently available concerning Aurora Kinase A invol-
sive cancer (Histopathology 2012, 61: 562-575), and authored the most recent national and international gui-
vement in serrated tumorigenesis.
delines for colorectal neoplasia pathological diagnosis (Dig Liver Dis 2011, 43: 344-55; Virchows Arch. 2011,
The current investigation is aimed at evaluating the involvement of the AURKA gene and protein in the early,
458: 21-30; Surg Endosc 2015) .
progressive and non-progressive steps of the conventional adenoma-carcinoma sequence and at clarifying their
His laboratory research has been in the field of intermediate biomarkers in the GI tract. He elucidated the
role in the serrated tumorigenesis of the large bowel.
morphogenetic links between mucosa cell proliferation and the clinical and pathological features of colorectal
neoplasia (Gastroenterology 1988, 94: 899-906; Cancer Res 1991, 51: 1917-1921; Cancer Res 1996, 56:
Research achievements:
4910-4916). He has identified the relationships between the morphological features of neoplasia and the geno-
We demonstrated that the AURKA gene is involved in the adenoma-carcinoma sequence of the large bowel, ac-
mic changes in human colorectal tumorigenesis demonstrating the role of microsatellite instability in inducing
ting solely in adenomas in which the malignant transformation actually occurs (progressive adenomas); in this
mucinous differentiation (Cancer Res 1996, 56: 5470-5474), of K-Ras and Apc gene mutations in the onset
setting, protein expression strictly parallels the increase in gene copy number. Conversely, the diploid status
of early adenomas (Am J Pathol 1998, 153: 1201-1209; Genes Chromosomes Cancer 2003; 37: 207-213; J
of the gene is maintained in non-progressive conventional adenomas and along the progression of serrated
Pathol 2004, 204: 193-199), and of the AURKA gene in the cancerization of serrated lesions (Hum Pathol.
neoplasia. Aurora Kinase A protein expression in serrated polyps is uncoupled from gene status and is likely to
2014,doi: 10.1016/j.humpath.2014.11.016). Mauro Risio has authored 120 full papers published in peer-
reflect apoptotic dysregulation.
reviewed journals.
Conclusions and perspectives:
FISH evaluation of AURKA gene status could therefore potentially discriminate between progressive and nonprogressive conventional adenomas of the large bowel. The clinical significance of the morphologically identifiable dysplasia in the natural history of serrated lesions has to be critically re-evaluated.
Selected references
Risio M. et al, Histological features of advanced colorectal adenomas detected by endoscopy and fecal immunochemical
test. Endoscopy. 2015 May 28.
Casorzo L, Dell’Aglio C, Sarotto I, Risio M. Aurora kinase A gene copy number is associated with the
malignant transformation of colorectal adenomas but not with the serrated neoplasia progression.
Hum Pathol. 2015 Mar; 46:411-8
Righi A, Sarotto I, Casorzo L, Cavalchini S, Frangipane E, Risio M. Tumour budding is associated with hypoxia at the
advancing front of colorectal cancer. Histopathology. 2015 Jun; 66:982-90
60 | Applied Clinical Research
Applied Clinical Research | 61
Candiolo Cancer Institute
Research topic:
Identification of potential targets in cancer of the biliary tract
Francesco Leone MD
Unit for the Study of Tumors of the Gastrointestinal Tract
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933503 - 3250
Fax. +39.011.9933524/3275
Development of new cancer therapies to improve the prognosis of biliary carcinomas,
a group of highly lethal malignances
Team
Renato Ferraris, Federica Colombi, Ilaria Depretis, Elisabetta Fenocchio, Roberto Filippi, Donatella Marino,
Giuliana Cavalloni, Caterina Peraldo Neia
Biographical Sketch:
New strategies in advanced biliary cancer treatment
Francesco Leone is Assistant Professor at the University of Turin, Department of Oncology. Since 2006 he is
coordinator of the activities of the multidisciplinary team for the treatment of digestive cancers at the Candiolo
Background:
Cancer Institute and coordinator of translational research projects in this field between the Medical Oncology
Biliary tract cancer (BTC) is a rare and lethal disease with very few therapeutic options. Previous studies sug-
Division and the Oncology Laboratory at the Institute. In colorectal cancer, the major area of interest is repre-
gest that Epithelial Growth Factor Receptor (EGFR) pathway activation could be involved in BTC pathogenesis,
sented by “conversion therapy” to maximize the possibility to offer surgery to metastatic patients (Crit Rev On-
envisaging a potential role of anti-EGFR monoclonal antibodies.
col Hematol. 2014 92:218-26, Cancer. 2013;119:3429-35). He realized a significant synergy also for the multidisciplinary treatment of locally advanced pancreatic cancer (Cancer. 2013;119:277-84) and, in the metastatic
Research achievements:
setting, he participated in the pioneering of modern immunotherapy concepts (Ann Oncol. 2014;25:1750-5).
Our group has designed and coordinated a multicenter randomized phase II clinical study to evaluate the effi-
In recent years, his main area of research has been the study of biliary tumors. He has contributed to exploring
cacy of the fully human monoclonal anti-EGFR panitumumab (P) in combination with standard chemotherapy
the feasibility of targeted therapies for these highly malignant cancers (Crit Rev Oncol Hematol. 2013;85:136-
(GEMOX) compared to GEMOX alone for the treatment of unresectable BTC with KRAS wild-type status (Vecti-
48, Clin Cancer Res. 2006;12:1680-5) and is currently engaged in the final analysis of a multicenter randomi-
BIL study, NCT01389414). The primary endpoint was to demonstrate that the P-GEMOX combination is able to
zed clinical trial of panitumumab in combination with chemotherapy for advanced biliary tumors, coordinated
prolong progression-free survival (PFS) from 6 months (estimated PFS of GEMOX arm) to 10 months. Enrol-
by the Candiolo Cancer Institute (ASCO GI Proceedings 2015). Given the unsatisfactory results of the anti-EGFR
lment in the study, which involved 10 Italian Cancer Centers, was completed in September 2013. On december
based strategy, he developed insights in new directions such as the evaluation of new chemotherapy agents
15th 2014 the database will be closed and final analysis will be published. Preliminary results demonstrated
(BMC Cancer. 2014;14:918.) and the identification, through extensive molecular analysis, of specific genetic
that the P-GEMOX combination showed a trend towards better PFS and response rates (RR) in KRAS wild-type
targets to be explored in future clinical trials (Genes Chromosomes Cancer. 2014;53:1033-40).
BTC patients as compared to GEMOX alone. Even in the case of positive results, it is clear that anti-EGFR therapy may be only a step closer to better control of the disease and that the search for other targets remains
an essential topic. To this aim, we have developed a large scale approach based on gene expression profiling,
genome sequencing, miRNA and proteomic profiling of primary BTC to identify new potential druggable targets
in these tumors. To build more suitable preclinical models to test new therapies, we are focusing on the xenopatient model. To date we have achieved significant results in preclinical models with the use of both targeted
agents such as Src inhibitors and alternative (non-target specific) chemotherapy such as ET-743. Recent advances in our work have demonstrated that in 9% of BTC a FIG-ROS fusion is detected. In particular, we have set
up a new, quick, specific, and sensitive PCR test to screen for the FIG-ROS1 fusion.
Conclusions and perspectives:
On these bases we are planning new trials in patients relapsing after standard therapies where treatment will
be driven by an extensive molecular analysis.
Selected references
Aglietta M et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in
chemotherapy-naive patients with metastatic pancreatic cancer. Lancet Oncology 2013, 14:981-8.
Leone F, et al. Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy
in patients with colon cancer and advanced liver metastases. The MetaPan study. Cancer. 2013, 119:3429-35.
Marino D, et al. Biliary tract carcinomas: from chemotherapy to targeted therapy. Crit Rev Oncol Hematol. 2013, 85:136-48.
Pignochino Y, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary
tract and gallbladder carcinomas. BMC Cancer. 2010, 10:631.
62 | Applied Clinical Research
Applied Clinical Research | 63
Candiolo Cancer Institute
Research topic:
Cell therapy for metastatic tumors
Fabrizio Carnevale-Schianca MD
Unit of Cell Therapy
E-mail: [email protected]
Phone. +39.011.9933623
Fax. +39.011.9933299
Application of new cell-therapy based strategies, to synergize with molecular targeted therapies
Team
Daniela Caravelli, Valentina Coha, Paolo Becco, Susanna Gallo
Biographical Sketch:
Hematopoietic Cell Transplantation (HCT): toward an immunological platform for cell and molecular therapy in
Fabrizio Carnevale Schianca has been working in the field of hematopoietic stem cell transplantation (HCT)
the treatment of metastatic refractory cancers.
since the time of fellowship (1997) accumulating robust clinical knowledge both in the biological rationale
and clinical management of this strategy. As oncology- fellow he contributed to the start-up of the clinical
Background:
unit of Medical Oncolgy at the Candiolo Institute (1998). At the end of his fellowship he spent 18 months at
Allogeneic HCT, coupling to high dose chemotherapy a powerful donor immunological anti-tumoral effect, is a
Fred Hutchinson Cancer Research Center mentored by Rainer Storb. In Seattle he worked in the clinic, gaining
curative therapy for many hematological malignancies. However in the past years its broader application has
deep experience of allogeneic HCT; in clinical research he has carried out studies on GVHD treatment and
been limited by two relevant obstacles: the first being represented by Graft versus host disease (GVHD) -the
classification (Biol Blood Marrow Transplant 2000;6:613, Bone Marrow Transplant 2009;44:739, Biol Blood
second being represented by the incapability of generating a specific graft versus tumor effect (GVT). Only when
Marrow Transplant 2009;15:749). Once back in Candiolo he led the opening of the Medical Oncology Stem Cell
it will be possible to achieve a complete control of GVHD along with the generation of a specific GVT, allogeneic
Transplant Unit (2001); this unit is now part of a large metropolitan network that was JACIE-FACT accreditad
HCT will accomplish its extraordinary curative potential. Our research is focused on the clinical application of
in 2013.
a strategy able to fully control GVHD and that transforms HCT into a safe platform for adoptive cell therapy.
In clinical research since his return he was dedicated to mechanistically demonstrating that allogeneic HCT
can generate a specific, long lasting graft versus tumor effect in hematological and solid tumors (Blood
Research achievements:
2006;107:3795, NEJM 2007;356:1110, Blood 2009;113:3375, Biol Blood Marrow Transplant 2009;15:326,
In regard to GVHD our group contributed to the study of conventional treatment and classification of this com-
Blood 2011;117:6721). In the last years his group efforts have been aimed at exploring strategies for control-
plication and is currently running an interventional study of post-transplant cyclophosphamide (PT-CY) as a
ling GVHD and transforming HCT in to a safe platform for specific anti-tumoral cell-therapies In this regard he
safe strategy for GVHD control. In this context in the first 30 patients treated we reported an extremely low rate
is collaborating with immunologists (Int Immunol 2008;20:841, J. immunother 2012;35:579). Since 2010 he
of acute GVHD and no incidence of cGVHD.
and his group have been involved in the constitution of a melanoma-unit (BJC 2014;110;1721, Cancer Invest
In regard to GVT (i) we at first revealed that following HCT it was possible to generate donor T cells specifically
2014;32:144). In metastatic melanoma, taking advantage of his experience in cellular therapies he is colla-
directed against patient-tumor antigens. (ii) We contributed to the demonstration that allogeneic HCT is an
borating with immunologists to project clinical trials aimed at combining targeted therapies and check-point
effective cell-therapy in the treatment of Multiple Myeloma. (iii) We have been involved in pre-clinical studies
modulators to adoptive cell therapy (Clin Cancer Res 2013;19:4347, Expert Opinion Biol Ther 2014;14:1259).
regardings to a specific form of cell-therapy derived from the generation and infusion of Cytokine-induced-Killer
cells (CIK). In regard to Cell therapy regulatory issues and Law: cell therapy clinical application will be allowed
only in Clinical centers that are JACIE-FACT accredited. Our Transplant center as part of the Turin metropolitan
transplant network was accredited in July 2013.
Conclusions and perspectives:
The introduction in the clinical scenario of a safe strategy for GVHD control will allow HCT fully explored to
be as a platform for tumor specific cell therapy and investigating if this platform might contribute to a future
integration of cell therapy and molecular therapies. We plan to design and conduct clinical trials of cell-therapy
Selected references
(CIK and tumor specific T-cells) in the context of the Turin metropolitan transplant network both in solid tumors
Gammaitoni L, et al. Effective Activity of Cytokine Induced Killer Cells against Autologous Metastatic Melanoma
including Cells with Stemness Features. Clin Cancer Res. 2013, 19:4347-58
(melanoma and sarcomas) and in hematological malignancies.
Todorovic M, et al. Ex Vivo Allogeneic Stimulation Significantly Improves Expansion of Cytokine-Induced Killer Cells
Without Increasing Their Alloreactivity Across HLA Barriers. J Immunother. 2012,35:579-586
Leuci V, et al.Transient proteasome inhibition as a strategy to enhance lentiviral transduction of hematopoietic
CD34(+) cells and T lymphocytes: implications for the use of low viral doses and large-size vectors.
J Biotechnol. 2011, 156:218-26.
64 | Applied Clinical Research
Applied Clinical Research | 65
Candiolo Cancer Institute
Research topic:
Integrated therapies for the treatment of sarcomas
Giovanni Grignani MD
Unit for Investigation and Therapy of Sarcomas
E-mail: [email protected]
Phone. +39.011.9933623
Fax. +39.011.9933299
Cooperative trials for new therapeutic approaches
Team
Ymera Pignochino, Sandra Aliberti, Lorenzo D’Ambrosio, Danilo Galizia, Federica Capozzi, Paola Boccone,
Sara Miano, Erica Palesandro, Marta Canta, Maja Todorovic
Biographical Sketch:
Integrated therapies for the treatment of sarcomas
Giovanni Grignani has been involved in clinical research focusing on the development of prognostic tools in oncohematology and later in the field of sarcomas. During his residency he worked on the identification of prognostic
Background:
factors to improve multiple myeloma and lymphoma stratification as well as on several phase II trials exploring
Bone and soft tissue sarcomas (B-STS) are a rare and heterogeneous group of tumors. As of today, a multidi-
innovative chemotherapy combinations. Since he moved to the Candiolo Institute, he has been actively involved
sciplinary treatment encompassing complete surgical removal of the tumor +/- chemotherapy and radiotherapy
in translational research in the field of stem cells and sarcomas. In particular, he deepened understanding the
cures roughly 50% of patients. Unfortunately, the most active chemotherapies may eradicate micro-metastatic
mechanisms of metastatic seeding of osteosarcoma (Clin Cancer Res 2005;11:490-7) identifying the CXCR4/
disease, but do not cure non-resectable disease. Several second- and further-line treatments have been tested
CL12 axis as one of the major determinants of the peculiar pattern of osteosarcoma diffusion. He took part
showing marginal activity at most. Therefore, innovative therapeutic strategies are urgently needed.
in several pivotal trials of target therapies and took advantage of his large experience to develop preclinical
models to test target therapies in sarcomas other than gastrointestinal stromal tumors (Cancer 2011;117:826-
Research achievements:
31). His group identified the role of the MAPK pathway (Clin Cancer Res 2013;19:2117-31) in osteosarcoma
We focused on the identification of key-pathways that can be exploited with innovative therapeutic tools. In osteo-
progression and, on this original finding, he demonstrated the activity of sorafenib and mTOR inhibitor in the
sarcoma we identified the role of the mTOR pathway as a mechanism of resistance to sorafenib and showed the
advanced stages of this tumor (Ann Oncol 2012;23:508-16 and Lancet Oncol 2015;17:1470-8).
possibility of hitting this pathway with an innovative target combination therapy with sorafenib and everolimus. In
In the last years, he set up a preclinical collaboration with immunologists in the attempt to overcome the intrin-
this context we ran and completed a phase II trial. We identified on several B-STS the expression of specific an-
sic limit of target therapies related to tumor heterogeneity. In this setting, he has recently published an original
tigens that can elicit a MHC-unrestricted T-cell immune-response. Thereafter, we demonstrated in B-STS patients
model to expand patient derived lymphocytes showing that so-called cytokine induced killer cells selectively kill
that we could sort and ex-vivo expand a specific T-cell sub-population endowed with antitumor activity directed
autologous sarcoma cells (Cancer Res 2014;74:119-29). In the forthcoming year this experience is going to be
against patients’ tumors. After ongoing AIFA protocol approval, a phase I/II trial will be run within the Italian Sar-
translated into the clinic in a phase I/II trial.
coma Group.
Response to treatment with sorafenib
and everolimus in patients affected by
advanced, high-grade, chemotherapyrefractory osteosarcoma. PET scan
performed at baseline (left) and after
two months of therapy (right).
Conclusions and perspectives:
The achieved results show the importance of dissecting B-STS heterogeneity to identify histotype specific Achilles’
heel. Moreover, we are developing a form of immunotherapy that can be combined with any of the multidisciplinary therapies that are the real backbone of sarcoma treatment. In perspective we look for an even greater
integration with the other immunotherapeutic tools directed to reactivating patient anti-tumor response. Secondly,
several new compounds with improved selectivity to targets are in development. We have built a successful partnership with several pharmaceutical industries based on clinical trials designed and conducted by our team. On
this ground, we will keep on joining international trials of important drugs, as we did with pazopanib, and investigating combination therapies based on our preclinical/translational research activity.
Selected references
Sangiolo D, et al., Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas. Cancer Res 2014, 74:119-29
Pignochino Y, et al., The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in
osteosarcoma preclinical models. Clin Cancer Res 2013, 19:2117-31
Stacchiotti S, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol 2012, 30:914-20
Grignani G, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of
standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 2012, 23:508-16
66 | Applied Clinical Research
Applied Clinical Research | 67
Candiolo Cancer Institute
Research topic:
Hyperthermic intraperitoneal chemotherapy (HIPEC)
Michele De Simone MD
Unit of Surgical Oncology
E-Mail: [email protected]
Phone. +39.011.9933449
Fax. +39.011.9933440
Treatment of peritoneal carcinomatosis
Team
Armando Cinquegrana, Patrizia Marsanic, Andrea Muratore, Demetro Siatis, Alfredo Mellano, Marco Vaira
Biographical Sketch:
Treatment of peritoneal carcinomatosis by surgical cytoreduction combined with HIPEC
Michele De Simone has always been interested in research of new technologies in Surgical Oncology. (Anticancer Res. 2001 May-Jun;21(3C):2243-8.). He focused his experience in the field of primary and metastatic
Background:
tumors taking an active part in many clinical research projects (Rev Recent Clin Trials. 2007 Jan;2(1):43-
Our clinical experience is focused on the treatment of peritoneal carcinomatosis and tumor recurrence. Since
8.) He developed research experience in treatment of peritoneal carcinomatosis (J Clin Oncol. 2004 Aug
1995, about 900 operations for peritoneal carcinomatosis have been performed; since January 2013 to date
15;22(16):3284-92). He is athor of more than 150 papers published in peer-reviewed Journals.
more than 150 patients with peritoneal carcinomatosis have been treated in our Istitute. Our operative unit is
specialized in the treatment of this kind of disease by cytoreductive surgery (CRS) combined or not with hyperthermic intraperitoneal chemotherapy (HIPEC) and secondary surgical cytoreduction of advanced cancers.
Research achievements:
In the last two years we have performed about 45 CRS + HIPEC (peritoneal mesothelioma = 8; colorectal carcinomatosis = 10; pseudomyxoma peritonei = 20; ovarian carcinomatosis = 6). Through the constant improvement of surgical and perioperative skills, we have achieved promising results in terms of long-term survival
(median overall survival of 58 months for peritoneal mesothelioma, 42 months for ovarian cancer, 55 months
for colorectal carcinomatosis, 144 months for PMP associated with a 10-yr overall survival of 80%) associated
with low perioperative morbidity and mortality rates. We have registered an overall major morbidity rate of 15%,
decreased to 6.7% considering only the last two years associated with no perioperative death. Since January
2013 in our Institution we have performed more than 100 surgical cytoreductions, which 65 for ovarian carcinomatosis. The mainstay of treatment is the attempt to achieve complete surgical cytoreduction, identified as
the most significant prognostic factor: in this regard we perform a high number of primary or interval debulking
surgeries with no macroscopic residual disease (CC-0) in a substantial number of patients. In cooperation with
medical oncology, considerating that the follow-up is too short, the results in terms of long-term outcome are
still being processed. We can assert that during the last two years we registered a major complications rate of
2-3% with no postoperative deaths. All the HIPEC procedures (45 cases) were carried out intraoperatively with
an original “semi-closed” technique. During the last years we have redefined our patient selection policy and
sought to restrict indications to patients with less advanced or less aggressive disease: the selection process for
CRS and HIPEC is critical and prognostic factors are required to identify patients who may most benefit from
these treatments. The standardization of the surgical technique borrowed from experience in the treatment of peritoneal carcinomatosis allows us to obtain good long-term results with limited costs and mean hospital stay time.
Conclusions and perspectives:
In order to perform a more careful selection of patients, we are investigating the practice of second look (technique) to identify patients that early presenting an higher risk of relapse; for that purpose we are, also, testing
the use of the liquid biopsy for the detection of circulating DNA. We are also investigating the possibility of
performing laparoscopic HIPEC on selected patients. Moreover, in order to evaluate achieved results, we intend
to participate, subject to approval by the ethics committee, in randomized controlled trials for the treatment of
peritoneal carcinomatosis of colonic and ovarian origin by cytoreductive surgery and HIPEC.
68 | Applied Clinical Research
Selected references
Caneparo A, et al. Contamination risk for operators performing semi-closed HIPEC procedure using cisplatin.
Eur J Surg Oncol. 2014, 40:925-9.
Cavaliere F, et al.Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis
treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter
study S.I.T.I.L.O.Eur J Surg Oncol. 2011, 37:148-54.
Baratti D, et al.Multicystic peritoneal mesothelioma: outcomes and patho-biological features in a multi-institutional
series treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).Eur J Surg Oncol.
2010 ,36:1047-53.
Applied Clinical Research | 69
Candiolo Cancer Institute
Research topic:
New strategies for breast cancer local-regional control
Riccardo Ponzone MD
Unit of Gynecological Oncology
E-mail: [email protected]
Phone. +39.011.9933036
Re-definition of local-regional breast cancer treatment according to the risk of relapse
Team
Franziska Kubatzki, Furio Maggiorotto, Alessandra Magistris, Francesco Marocco, Stefania Renditore,
Alessandro Rivolin, Paola Sgandurra, Salvatore Carlucci
Biographical Sketch:
Strategies for breast cancer loco-regional control
In 1987 and 1988, he was employed in the laboratories of the Wistar Institute and Children Hospital of Philadelphia, U.S.A., where he acquired the basics of Molecular Biology and was involved in research projects on
Background:
hyperphenylalaninemia and pterin metabolism (J Inher Metab Dis 1989; 12: 162)
The prevention and early detection of local-regional relapses requires a better understanding of the complex
After graduation, he was actively involved in the clinical and research activities at the Dept. of Gynecological
relationship between the primary tumor and its metastatic dissemination. For optimal breast cancer care new
Oncology, University of Turin, Italy, where he specialized in 1997. Over these years, he co-authored several pa-
advancements in surgery and radiotherapy must be integrated in to the complex and rapidly evolving armamen-
pers on the prognostic significance of the family of kallikreins in breast and ovarian cancer (Cancer Res 1995;
tarium of targeted systemic therapies.
55:2104-2110).
In 1995 – 1996 he attended as clinical research fellow the Royal Marsden and University College Hospital of
Research achievements:
London, UK, where he conducted clinical trails on innovative endocrine therapies for breast cancer (Br J Cancer
The influence of several treatment-related (accelerated partial radiotherapy, width of surgical margins, endocri-
1999; 79: 311-5), and developed a personal interest is the clinical issues related to hereditary breast and ova-
ne therapy with aromatase inhibitors), tumor-related (lobular histology, miR148b expression) and host-related
rian cancer (Eur J Cancer 1998 ; 34 : 966-967).
parameters (body mass index, polymorphisms at the CYP19A1 locus) on the likelihood of breast cancer relapse
From 1999 to 2009 he was appointed attending Gynaecologist at the Mauriziano Hospital of Turin and at the
have been examined. The available data and the new hypotheses on the relationship between loco-regional con-
Institute of Candiolo. During these years he focused his research activity on the adjuvant (Ann Oncol 2006; 17:
trol and survival have been reviewed from a breast surgeon’s standpoint.
1631–1636) and surgical (J Clin Oncol. 2009; 27:5547-51) therapy of breast cancer. In 2010 he was appointed
Director of the Division of Gynaecological Oncology at the Institute of Candiolo.
Conclusions and perspectives:
His current research interests are devoted to tailoring loco-regional breast cancer treatments (Eur J Cancer.
The current understanding of breast cancer natural history points towards the existence of a complex interplay
2012;48:2311-8) and minimizing their side effects (Ann Surg Oncol. 2012 Nov;19:3755-61). He has also conso-
between loco-regional and systemic processes. Loco-regional recurrences are associated with decreased overall
lidated his expertise in pelvic surgery, with a particular interest in molecularly-based and innovative treatments
survival and this may be related to a complex relationship between circulating tumor cells, re-seeding of the
of ovarian cancer. In his career, he has performed more than 4500 breast and pelvic surgeries and has authored
primary tumor site and several metabolic effects linked to the act of surgery. A re-definition of local-regional
more than 90 papers published in international peer-reviewed journals, as well as book chapters and national
breast cancer treatment according to the risk of relapse based on improved bio-molecular characterization of
guidelines.
the tumor is required to tailor the adoption of diagnostic tools, loco-regional and systemic treatments.
Selected references
Biglia N, et al. Role of re-excision for positive and close resection margins in patients treated with breast-conserving
surgery. Breast. 2014, 23:870-5
Ponzone R, Baum M. Loco-regional therapy and breast cancer survival: searching for a link. Breast. 2013, 22:510-4.
Montemurro F, et al. Omission of axillary dissection after a positive sentinel node dissection may influence adjuvant
chemotherapy indications in operable breast cancer patients. Ann Surg Oncol. 2012, 19:3755-61.
D’Alonzo M, et al. Clinical and radiological predictors of nipple-areola complex involvement in breast cancer patients.
Eur J Cancer. 2012, 48:2311-8.
70 | Applied Clinical Research
Applied Clinical Research | 71
Candiolo Cancer Institute
Research topic:
Applications of Computer Assisted Diagnosis (CAD) in Radiology
Daniele Regge MD
Image and Data Processing Laboratory (IDP)
E-mail: [email protected]
Phone. +39.011.9933370
The diagnostic imaging, improved by CAD systems, allows tumor diagnosis to be brought forward to an
early asymptomatic phase
Team
Ilaria Bertotto, Delia Campanella, Gabriele Chiara, Andrea Crivellaro, Veronica Deantoni, Valentina Giannini,
Antonio Manca, Laura Martincich, Simone Mazzetti, Filippo Russo
Biographical Sketch:
Computer Aided Diagnosis (CAD) applications in Radiology
Dr.Regge is the Director of the Radiology Unit at the IRCCS in Candiolo and he supervises a multidisciplinary
team, which investigates advanced medical imaging technologies. The group seeks to enhance cancer diagno-
Background:
sis by means of Computer Aided Diagnosis (CAD) systems. His major scientific accomplishments are: (i) He
High resolution images of the human body are generally obtained by Computed Tomography (CT) or Magne-
is internationally recognized for his contributions to the CT-colonography field, being involved in clinical trials
tic Resonance (MR) imaging. CT Colonography is an example of such detailed imaging in which data from a
and coordinating the largest european multicentre study (JAMA;301:2453-61). This study, together with the
CT scanner are processed by dedicated software to obtain a 3D representation of the colon from inside the
ACRIN-6664, lead to the introduction of CT-colonography into the guidelines of the American Cancer Society
intestinal lumen in a similar way to a conventional endoscope view. On the other side, MR imaging has shown
as a screening test for colorectal cancer. (ii) He is PI of the first large world mass screening trial with CT-colo-
promise in localizing cancers, because of its intrinsic high soft-tissue resolution, and combining two or more
nography conducted in Piemonte and in the province of Verona (http://clinicaltrials.gov/show/NCT01739608)
image modalities can improve the sensitivity of MR tests. However the more variables are introduced the more
(iii) He is active in the development and clinical validation of CAD systems for diagnosis of colorectal, breast
difficult it is to integrate all available information into one reliable final report, even for an experienced reader.
and prostate cancer (Invest Radiol;49(3):173-82). (iv) He has given important contributions to the field of
To deal with these complex problems, computer aided diagnosis systems (CAD) have been introduced to help
multiparametric-MRI, which helped change the diagnostic pipeline of prostate cancer(J Urol;192(1):60-6). He
radiologists in diagnosing disease.
is the author of more than 100 peer-reviewed publications and more than 300 scientific contributions in national and international congresses, and he has been moderator or invited speaker at more than 250 conferences
Research achievements:
worldwide. Dr.Regge has been PI of several supported research projects, and he is part of the faculty of the
The research group has developed a CAD able to produce quantitative maps of the prostate, providing mali-
European School of Radiology, founding Member and president elect of the ESOI, board Member and Secretary
gnancy probability information with useful data that might be difficult to assess visually from MR scans. Regar-
of the European Society of EuSoMII and President of the Italian Chapter of Imaging Informatics.
ding the CAD colon, diagnostic performance of CT colonography in individuals at increased risk of colorectal
cancer was investigated, and further studies are being conducted using the innovative dual energy technology,
to generate so-called virtual non-contrast images. Finally, within the CAD-breast project, we have implemented
a fully automatic method for detecting blood vessels in dynamic contrast-enhanced breast MR images. The method could be used to reduce labeling of vascular voxels as parenchymal lesions in the CAD breast, and it could
also be used to evaluate the pathological response after neoadjuvant chemotherapy.
Conclusions and perspectives:
Recently, our group has published the results obtained using the CAD system for CT colonography screening. In
these studies it has been demonstrated that, at the 6-mm threshold, sensitivity of unassisted reading (79.6%)
increased significantly with the use of both second-reader CAD (86.0%) and a double-reading paradigm in which a
first-reader CAD is followed by a fast 2-dimensional review (89.2%). Besides, the latter required less reading time
than that for second-reader CAD (Δ118 seconds) and was 59 seconds longer than unassisted reading. Conversely,
Selected references
the CAD prostate is still in a preliminary development phase. However, preliminary results obtained on a cohort
Porpiglia F,et al. The roles of multiparametric MRI, PCA3, and PHI: which is the best predictor of prostate cancer after
a negative biopsy? Results of a prospective study. J Urol. 2014, pii:S0022-5347:00052-4
of 33 patients reported a sensitivity of 94%, with a median number of FP per patient equal to 1, and 2 in the
peripheral and central zone, respectively. Finally, regarding the breast project, we obtained promising results in
detecting most vessels identified by an expert radiologist. Improving CAD performance will stimulate diffusion of
such systems in clinical workflows, helping radiologists in detecting cancer, in particular when diagnosis is time
consuming and requires deep expertise. A new branch of research is now focusing an assessing the role of CAD in
Iussich G, et al. CT colonography: preliminary assessment of a double-read paradigm that uses computer-aided
detection as the first reader. Radiology. 2013, 268:743-51
Regge D, et al. Efficacy of computer-aided detection as a second reader for 6-9-mm lesions at CT colonography:
multicenter prospective trial. Radiology. 2013, 266:168-76
supporting prostatic MR-guided biopsy, and in estimating tumor aggressiveness by integrating the Gleason Score
with imaging, in order to better stratify patients and personalize treatments.
72 | Applied Clinical Research
Applied Clinical Research | 73
Candiolo Cancer Institute
Research topic:
“Personalized” radiation-therapy based on genetic,
biological, and “theragnostic” parameters
Pietro Gabriele MD
Unit of Radiotherapy
E-mail: [email protected]
Phone. +39.011.9933714
Fax. +39.011.9933754
Adapting radiotherapy treatment to the modern concept of “personalized medicine” (“Precision radiotherapy”)
Team
Gaetano Belli, Gabriella Cattari, Marco Gatti, Gabriele Petrilli, Antonia Salatino, Antonella Suma,
Domenico Gabriele
Biographical Sketch:
“Personalized” Radiation-therapy based on genetic, biological, statistical and “theragnostic” parameters.
Pietro Gabriele is an expert in Radiation Oncology with 3 medical specializations (Radiology 1979, Oncology
1982 and Otolaryngology 1987); director of Radiotherapy at Mauriziano Hospital (1997), of Sardinia Radio-
Background:
Oncology Department (2008) and from 2010 of Radiotherapy in Candiolo. His expertise started with head
The improved IMRT techniques (Intensity Modulated Radiation Therapy) allow the use of high doses, perfectly
and neck cancers, participating in the first Italian phase III trial of Radiochemotherapy for nasopharynx cancer
“sculpted” on the areas that are going to be treated. A further improvement of radiation treatment is provided
(JCO, 1988, 6: 1401); after that he cooperated in multicenter studies of head and neck cancers (Otol H&N
by “daily image control” based on the IGRT technique (Image Guided Radiotherapy). Genomic information and
Surg 2000, 123: 630, Int J Radiat Oncol Biol Phys 2005, 61: 762). He started studies of hyperthermia (1984)
“theragnostic” data allow the defining models to optimize the use of radiotherapy, in order to personalize tre-
publishing results on preclinical hyperthermia (Cancer Res 2003, 63:1500), hyperthermia alone in recurrent
atment.
cancers (Tumori, 1989, 75:284 - Cancer 1990, 66:2191), hyperthermia-radiotherapy on parotid cancer (Cancer
1995, 75:908) and in recurrent breast and melanoma (Int J Hyperthermia, 2009, 25: 189). In 2011-12 he beca-
Research achievements:
me board member of the European Society of Hyperthermic Oncology and in 2014 President of the 29° ESHO
(i) We have proved - in collaboration with the cancer stem cell laboratory - that ionizing radiation (IR) leads to
congress in Turin. He performed studies on dose escalation in prostate cancer and published on radiation set-
the expression of an oncogene (Met) involved in invasion and metastasis control; this data contributes to the
up (Radiother Oncol 2006, 80:363), IGRT (Stralenther Onkol 2011, 187: 473), and radiation risk nomograms
‘vexata questio’ debate about the possible radiotherapy side effects on metastasis sprouting. (ii) We performed
(Int J Radiat Oncol Biol Phys 2012, 82:1952, Radiother Oncol 2009, 93:197 and 2012, 103:252). From 1999
a feasibility study on large fields, using Tomotherapy. (iii) A controlled clinical trial on IMRT-IGRT treatment
he is member of the National Institute of Health board for Quality Assurance in Radiation Oncology (Tumori,
protocols for head and neck tumors and recurrences, and three studies on prostate cancers are in progress.
2009, 95: 467, Radiother Oncol 2007, 82:191 and Crit Rev Oncol-Hematol 2009, 70:24). To date (January
(iv) We are contributing to an international multicenter randomized phase III clinical trial on locally advanced
2015), he is author of more than 140 papers published in peer-reviewed journals.
rectal cancer. (v) We are leading the european project “Computational Horizons in Cancer” to create a predictive
nomogram of prognosis.
Conclusions and perspectives:
We plan (i) to evaluate the possible impact of genetics and molecular biology data on radiotherapy of Glioblastoma Multiforme (GBM). The preclinical research will be implemented by “xenopatients” (immunocompromised
mice transplanted with GBM of single patients, see above); (ii) to develop personalized radiotherapy treatment
of pancreas cancer, of clivus cordoma, of pleural mesothelioma and of gynecological tumors; (iii) to implement
treatment protocols by microwaves and radiofrequencies and by radiochemo-hyperthermia. This information
will be the basis for personalized treatment by Tomotherapy , performing ‘Adaptive Radiotherapy’ treatment.
Selected references
Gatti M, et al. Accelerated partial breast irradiation using 3D conformal radiotherapy: toxicity and cosmetic outcome.
Breast. 2013, 22:1136-41.
Valdagni R, et al. Increasing the risk of late rectal bleeding after high-dose radiotherapy for prostate cancer: the case
of previous abdominal surgery. Results from a prospective trial.
Radiother Oncol. 2012, 103:252-5.
Zucca S, Carau B, Solla I, Garibaldi E, Farace P, Lay G, Meleddu G, Gabriele P. Prostate image-guided radiotherapy
by megavolt cone-beam CT. Strahlenther Onkol. 2011, 187:473-8.
74 | Applied Clinical Research
Applied Clinical Research | 75
Candiolo Cancer Institute
Research topic:
Personalized medicine driven by
nuclear molecular imaging in cancer patients
Teresio Varetto MD
Unit of Nuclear Medicine
E-mail: [email protected]
Phone. +39.011.9933792
Providing personalized molecular imaging strategies in cancer patients
Team
Manuela Racca, Paola Scapoli, Valeria Pirro
Biographical Sketch:
Providing Personalized Medicine with Nuclear Molecular Imaging in Cancer Patients - PET/CT in early evalua-
Teresio Varetto has more than 25 years’ experience in all diagnostic and therapeutic activities in Nuclear
tion of cancer treatment response and targeting resistance to molecular therapies.
Medicine. During his career he has been a pioneer in the introduction of new diagnostic radiopharmaceutical
methodologies in Cardiology (J Am Coll Cardiol, 22 (1993), pp. 1804–1808 – Q J Nucl Med Mol Imaging. 2005
Background:
Jun;49(2):171-91) and in Oncology (Eur J Nucl Med Mol Imaging 2005 Aug- 19;32(8):937-42). Since 1998
Early differentiation between responders and non responders is a very important issue for the management of
he is Professor at Turin University Postgraduate Specialization School in Nuclear Medicine and Postgraduate
cancer patients. Wide evidence exists that FDG-PET can predict outcomes for many tumor types very soon after
Specialization School in Hospital Pharmacology. As Senior Expert in Nuclear Medicine at International Atomic
conventional systemic chemotherapy is started. In particular compared with cytotoxic chemotherapy, many
Energy Agency he accomplished Technical Cooperation Expert Missions in several African Countries collabo-
novel targeted therapies result in disease stabilization rather than tumor shrinkage. The activity of these novel
rating in the creation and dissemination of Nuclear Medicine Units and giving lectures and counseling at the
agents might, therefore, be better reflected by changes in molecular features of the tumor rather than reduction
local University Hospitals.
in size or volume. Recent prospective studies show that a change in tumor glucose activity (measured with FDG
As chairman of the Continuing Medical Education Committee of the UEMS European Board of Nuclear Medi-
PET standard uptake value-SUV) is a significantly more accurate parameter than a change in size in assessing
cine he is in charge of accreditation of International educational activities. (Eur J Nucl Med Mol Imaging 2013
histopathological response to neoadjuvant therapy in patient with GIST and high grade soft tissue sarcoma.
Feb; 40(3):470-4; Eur J Nucl Med Mol Imaging 2014 Jan;41(1):191-6; Eur J Nucl Med Mol Imaging 2014 Nov
31;41(11):2169-73). Member of the Executive Board of the Italian Association of Nuclear Medicine and Mo-
Research achievements:
lecular Imaging since 2000, he is Chairperson for CME in Nuclear Medicine at the National level. Since 2008
The PET imaging facility has been qualified by CoreLab Partners, Inc. for the submission of Nuclear Medicine
as Director of the Nuclear Medicine Department at the Candiolo Institute for Cancer Research he has been
and PET images of the patients who are enrolled in the CAUY922A2109 study. The aim of this study is to eva-
involved in research projects aimed at provide personalizing medicine to cancer patients as the use of PET/CT
luate the efficacy of AUY922 in combination with Trastuzumab in patients with locally advanced or metastatic
in early evaluation of cancer treatment response and targeting resistance to molecular therapies.
HER2-positive breast cancer that has progressed after or during at least one Trastuzumab-containing regimen.
Conclusions and perspectives:
Research goals will be to assess the value of metabolic imaging with PET in predicting response to therapy,
targeting resistance to molecular therapies, improving personalized therapy and prognosis.
Selected references
Evangelista L., Redana S., Racca M., Geuna E., Vinante L., Zago G., De Carolis V., Ghiotto C., Saladini G., Varetto
T. FDG Avidity at PET/CT During Adjuvant Hormonal Therapy in Patients With Breast Cancer. Clinical nuclear
medicine. 2014, 39:e135-41.
Varetto T, Durval C. The new UEMS-EACCME criteria for accreditation of live educational events (LEEs): another
step forward to improve the quality of continuing medical education (CME) in Europe. European Journal of Nuclear
Medicine. 2014, 41:191-6.
Varetto T, Durval C. Continuing Medical Education Committee and UEMS-EACCME.
European Journal of Nuclear Medicine. 2013, 40:470-4
76 | Applied Clinical Research
Applied Clinical Research | 77
Candiolo Cancer Institute
Research topic:
Personalized therapies in Medical Oncology
Massimo Aglietta MD
Medical Oncology
Full Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933628
Fax. +39.011.9933299
A new avenue of cancer therapy
Team
Marco Fizzotti, Lucia Garetto, Cinzia Ortega, Veronica Prati, Delia Rota Scalabrini, Giorgio Valabrega, Fiorella
Ruatta, Celeste Cagnazzo, Caterina Aversa, Rosa La Face, Sofia Genta, Rossella Martinello, Gloria Mittica,
Sonia Capellero, Luca Crotto, Marta Fenoglio
Biographical Sketch:
Implementation of clinical trials based on the identification of specific molecular targets on tumor cells.
Massimo Aglietta started his scientific career working in preclinical models of human tumors with the aim
of developing rational chemotherapeutic schedules based on tumor cell kinetics (Cancer Res, 39:2727-32,
Background:
1979). A logical pursuit of these studies has been the characterization
Target therapy represents the new avenue of cancer therapy. Although important results have been obtained
and neoplastic hemopoietic progenitor cells (Cancer Res, 40:2507-11, 1980; Blood, 67:789-95, 1986). These
with some tumors, on the whole the expected results have not been obtained. In most cases, even when tumor
preclinical studies led to the development of phase I/II clinical protocols that contributed to a rational sche-
progression is blocked by targeting a specific molecular alteration, resistance to treatment will eventually deve-
duling of hemopoietic growth factors to allow dose dense
lop. To understand the reason for drug resistance a continuous interaction between the clinic and the laboratory
Invest, 83:551-7, 1989; Blood, 82:2054-61, 1993; Cancer, 72:2970-3, 1993; Eur J Cancer 31: 46-9, 1995).
is needed. The analysis of the evolution of tumor genotype and phenotype during treatment is the only way to
This background was also behind the phase II protocols that explored the potential of stem cell transplan-
improve our capacity to treat tumors.
tation outside hemopoietic malignancies like colon cancer and sarcomas (J Clin Oncol, 15:2150-6, 2002;
of the growth pattern of normal
chemotherapy regimens in solid tumors (J Clin
Blood, 107: 3795-803, 2006; Nature Clin Practice Oncol (Review), 5: 256-267, 2008).
Research achievements:
Serving as Director of the Medical Oncology Unit he has continued to pursue the objective of building cli-
Our units have been focusing mainly on the treatment of sarcomas, breast and digestive tract carcinomas,
nical trials based on strong preclinical backgrounds. Of relevance:
becoming a referral centre for these diseases. The breast unit recently became autonomous. The secondary
of resistance to anti HER-2 therapy in breast cancer (Review in: Ann Oncol, 18: 977-984, 2007;
projects (see below), dealing with the single diseases, will detail the results obtained. These results derive from
24:1740-8, 2013); 2) the preclinical studies in bilio-pancreatic cancer that led to the development of
a continuous interaction between the laboratory (both the unit’s lab and the other labs of the Institute) and the
II clinical trials to evaluate the antitumor activity of treatments that combine chemotherapy with monoclonal
clinic. This made possible the implementation of clinical trials designed and conducted on the basis of hypo-
antibodies directed anti EGFr or anti CTL-4 (Ann Oncol, 25: 1750-5, 2014; Review in: Crit Rev Oncol Hematol,
theses generated at the bench and translated to the bedside.
85:136-148, 2013; Crit Rev Oncol hematol, 92: 218-, 2014) ; 3) Preclinical studies in sarcoma and melano-
1) the studies on
the development
Ann Oncol,
phase
ma revealed molecular alterations involved in tumor progression. Molecularly driven clinical trials have been
Conclusions and perspectives:
successfully conducted (Cancer, 115:2980-7, 2009; Cancer, 117:826-31,2011; Ann Oncol, 23: 508-16, 2012,
To continue our effort at designing clinical trials based on a thorough analysis of the tumor and of its interac-
Lancet, 379: 1879- 86 , 2012; Clin Cancer Res,. 2117-2031, 2013, Lancet Oncol, 16: 98-107, 2015).
tion with the host. The secondary projects will detail the ongoing projects coordinated by our Unit. Moreover,
We are now continuing to translate into the clinic the discover of basic research (Clin Cancer Res. 19:4347-58,
strict cooperation is ongoing with the other leading clinical oncological institutions in Italy and in Europe.
2013; Cancer Res. 74: 119-29, 2014). We are engaged in clinical trials exploring the best way to integrate
immunotherapy with chemotherapy and molecular based therapy. Massimo Aglietta is author of more than
250 papers in peer reviewed journals
Selected references
Grignani G, et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after
standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncology. 2015, 16:98-107
Aglietta M, et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in
chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol. 2014, 25:1750-5
Leone F, et al. Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy
in patients with colon cancer and advanced liver metastases. The MetaPan study. Cancer. 2013, 119:3429-35
78 | Applied Clinical Research
Applied Clinical Research | 79
Candiolo Cancer Institute
Research topic:
Clinical Services
Piero Fenu M.D.
Direttore Sanitario
E-mail: [email protected] - Phone. +39.011.9933618
The head of the department of clinical services participates in the strategic planning process and contributes, with the formulation of proposals and opinions, to
hospital management. He directs health services and is responsible for hygiene and
prevention (hospital infection control and environmental hygiene).
The clinical service office monitors the appropriateness of admissions, the hospital stay lenghts, the average
weight of the so called ‘case mix’ and supervises the waiting list. He coordinates with the Operation Department
the proper use of spaces and the timely flow of goods and services. The clinical service office:
(i) is in charge of the control of the fulfillement of results obtained within the assigned objectives; (ii) coordinates the facilities of the hospital including the provision of appropriate protocols; (iii) defines strategies and
guidelines for extraordinary and/or urgent intervention; (iv) advises on building planning regarding further
hospital expansion; (v) Supervises the ‘conventional’ agreements and the related relations with the University.
Michele Stasi, M.D.
Medical Physics
E-mail: [email protected] - Phone. +39.011.9933708
“Safe” dose escalation with Tomotherapy: from advanced segmentation to adaptive doseTumor segmentation based on multi-modal imaging, sophisticated patient
specific Quality Assurance and treatment options such as Helical Tomotherapy,
IMRT, IGRT, and adaptive radiotherapy.
Giovanni Galatola, M.D.
Gastroenterology
E-Mail: [email protected] - Phone +39.011.9933410
The Gastroenterology Unit at IRCC is a dedicated provider of a wide range of diagnostic and therapeutic endoscopic procedures for the upper and lower gastrointestinal tracts, and is involved in the clinical care of patients with chronic viral
hepatitis and those with gastrointestinal disorders in the medical oncology setting.
Antonino Sottile, M.D.
Direttore Operativo
and Laboratory Medicine
E-Mail: [email protected] - Phone +39.011.9933038
This Unit is mainly devoted to patient diagnosis and treatment. Nevertheless, a
strong effort is made in performing analysis supporting clinical trials as well as
translational research. The laboratory is also engaged in its own research activity
aimed at developing and testing novel diagnostic procedures. A special emphasis
is placed on the analysis of prostate cancer markers.
Felicino De Bernardi, M.D.
Cancer Pain
E-Mail: [email protected] - Phone.+39.011.9933018
Cancer pain significantly affects the physical, psychological and emotional components and quality of life of the individual. Our goal is the optimisation of pain
relief through a patient-centred approach with particular attention to quality of
life, personalized care and application of the newest drugs and treatments.
80 | Clinical Services
Alessandro Bonzano, M.D.
Cardiology
E-Mail: [email protected] - Phone +39.011.993.3888
The Cardiology Unit at the IRCCS is engaged in the prevention, diagnosis and
treatment of cardiotoxicity caused by old chemotherapy drugs (anthracyclines,
5-fluorouracil) and new agents ( trastuzumab). Doppler echocardiography and biomarkers as troponin are used to identify early damage of the heart during chemotherapy. A growing experience in the field of Cardioncology has lead to tailored
treatment for cancer patients with cardiovascular complications.
Franca Goffredo, M.D.
Pharmacy
E-Mail: [email protected] - Phone +39.011.9933261
The Pharmacy Unit manages drug/medication related activities and issues for all
IRCCS wards (drug lifecycle). Some of these activities include supplying , storage, distribution, drug information, therapeutic policy/formulary. Preparation of
chemotherapy and supportive care medications for in and out patients, together
with investigational drug management and research support (including regulatory
issues) are the main and distinguishing activities , which are enhanced by integrated
IT and automation. The staff is an active partner of the University in the pharmacy
education and training programmes
Clinical Services | 81
Educational Activities: the Chiron international program
The Institute provides teaching and training programs in
the area of basic and clinical cancer research.
These are listed in order of increasing complexity as
follows:
(a) Courses.
(b) Seminars and Workshops. (i) “Lezioni Magistrali”:
one in basic research and one on clinical research, each
held by eminent scientists. (ii) Formal seminars: throughout the year, divided among basic and clinical research, held by external invited speakers. (iii) Progress reports held by members of the Institute, once a week for
48 weeks of the year. (iv) International Workshops, on
either basic or clinical research. These workshops are
usually organised within the framework program of the
European Molecular Biology Organization (EMBO) and
of the European Society for Medical Oncology (ESMO).
(c) Research Doctorates aimed at the training of basic
and clinical research.
(d) Master in Molecular Oncology.
(e) Post-doctoral programs.
2014 Courses
The scientific and professional advanced teaching is based on lectures and practical courses.
These last from one to three days and are aimed at newly graduated MD or PhD, as well as to Physicians, as
refresher courses.
• ESOI Workshop 2014 “Imaging Cancer: Staging and response to therapy”, 13-14 November, 2014
• Course “Transanal Total Mesorectal Excision (taTME) in rectal cancer”, 27-28 October, 2014
• 29th Annual Meeting of the European Society for Hyperthermic Oncology, 11-14 June, 2014
• Transanal Total Mesorectal Excision (taTME) in rectal cancer, 29-30 May, 2014
2014 IRCC Cancer Conferences
• IRCC International Conference - “Molecular Clinical Oncology ‘Precision Medicine’”, 4-5 October, 2014
2014 Seminars
• Applying Bioinformatics to Clinical Research - Dr. Giovanni Crisafulli - March 19, 2014
• Improved risk stratification in myeloma using a microRNA-based classifier - Dr. Luca Agnelli -March 31,
2014
• Diagnosis of tumor progression in the clinical setting - Dr. Lisa Ryden - April 1, 2014 - 16:00
• Background & Perspectives in Bioinformatics - Dr. Andreas Buness - April 28, 2014
• Molecular stratification and molecular monitoring in breast cancer - Prof. Carlos Caldas - April 30, 2014
• Spectacular Advances in Drug Development: Melanoma as Mode System for both Targeted and Immunotherapeutic Approches - Prof. Alexander Eggermont - June 12, 2014
• Multimarker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer
Prof. Alain Thierry July 10, 2014
• Interrogating protein dynamics within living cells using protein-based reporters derived from
NanoLuc®Luciferase - Dr. Matt Roberts - September 11, 2014
• Cancer Evolution: Causes and Consequences - Prof. Charles Swanton - September 23, 2014
• Reflections on the Global Cancer Research Landscape - Dr. Margaret Foti, PhD, MD - November 25, 2014
82 | Educational Activities
PhD Programs
The Institute offers four different PhD programs.
(a) PhD in Molecular Medicine (Cell Sciences and Technology): a four-year course (under the auspices of the
University of Torino) open to young graduates in Medicine, Biological Sciences, Biotechnology, Chemistry, and
Pharmacology. It is aimed at training for basic and translational research in biomedical sciences.
(b) PhD in Complex Systems and Post Genomic Biology: a three-year course (under the auspices of the University of Torino) aimed at training graduates in the fields at the interface of medicine, life sciences, mathematics
and physics.
(c) PhD Program in Biomedical Sciences and Oncology: a four-year course (under the auspices of the University of Torino) open to graduates in Medicine, and Biological Sciences and mainly aimed at training clinical
researchers.
(d) PhD program in Oncological Sciences: a three-year course (under the auspices of the Catholic University
of Milano-Roma) aimed at exceptionally talented graduate students to be trained in cutting-edge oncological
research at the highest level.
Graduate students are provided with an individual tailored guidance program and required to rotate through a
number of laboratories to learn different research techniques collaborating with world-class scientists. Career
counselors help students to investigate job types, develop curriculum vitae and resumes, and refine interview
skills. After completing the PhD program students are encouraged to participate in internship opportunities in
both basic or clinical research, technology transfer, science policy, and management.
All programs are open to Italian and foreign students. Fellowships are provided on a competitive basis
Post-doctoral Programs
IRCC International Cancer Research Training Program
This scheme employs scientists of all nationalities to improve scientific exchange between the Institute’s researchers and colleagues who have matured qualifying experience in foreign institutions. The research field is at in
the interface between molecular biology and medicine, referring in particular to today’s problems in molecular
oncology.
The Marie Curie European Training Center
The European Commission has recognized IRCC as a qualified center for training young researchers in the
experimental medical science field. Within the framework of the program, IRCC employs in rotation graduate
students from member states for periods varying from six months to two years in the research laboratories.
Molecular Oncology Master
The Institute, under an agreement with the University of Torino, also offers a two-year Master in Molecular Oncology aimed at providing clinical oncologists, surgical oncologists, radiologists, radiotherapists, and pathologists
with up-to-date knowledge of cancer biology and genetics as well as of the novel diagnostic and therapeutic
(e.g. precision medicine) approaches that arose from latest molecular and genomic information.
Educational Activities | 83
Core Facilities
The ‘Xenopatients’ Platform for Experimental Oncology.
Andrea Bertotti, M.D., PhD
Assistant Professor
University of Torino Medical School
E-mail: [email protected]
Phone. +39.011.9933242
Immortalized cancer cells exhibit a genetic drift, a biological compliance and
phenotypic features different from original cancers in patients. Another drawback of
the use of continuous cell lines is that the catalogue of currently available models is
inevitably finite, and possibly poor for some tumour subtypes. Therefore, experiments with cell lines
cannot recapitulate the wide heterogeneity of human malignancy that occurs among individuals on
a population basis. One way to tackle this issue is to perform population-based in vivo studies by
using large series of human cancer specimens directly transplanted into mice. This setting can be
exploited as a bridgehead to unravel the genetic and biological complexity of cancer, as a prelude
for the identification of novel therapeutic targets and unanticipated pharmacological approaches.
XPErO provides researchers with a collection of liver metastases from colorectal cancer that have been
systematically transplanted in immunocompromised mice to obtain stable tumor lines (xenopatients),
which are available for any kind of in vivo/ex vivo study. This resource builds on three main cornerstones:
(i) The viable biobank of colorectal cancer liver metastases. An institutional effort has led to the collection
and implantation of more than 500 samples of metastatic colorectal carcinoma. This resource allows us to
select the appropriate candidates among more than 300 experimental models, based on clinical, biological,
genetic or gene expression traits. This, in turn, is instrumental for achieving the appropriate statistical
power for any kind of translational study, even if focused on relatively small tumour subpopulations.
(ii) The ‘Xenopatients’ experimental platform for in vivo drug screening. We have implemented a dedicated
experimental pipeline that required the recruitment of ad-hoc personnel and the development of a specific
workflow. The possibility to exploit trained staff and to apply robust standard operating procedures (SOPs)
to experimental work confers high added value to research projects, in terms of both cost effectiveness and
efficiency of the resources used. (iii) The Laboratory Assistant Suite package for data management and
analysis. We have developed a web-based bioinformatics platform that assists biomedical researchers in
multiple activities, which range from tracking data generation and SOPs execution to the management of
multidimensional molecular profiles and complex data integration (The Laboratory Assistant Suite or LAS,
http://devircc.polito.it/wordpress/). This kind of informatics support provides invaluable benefit by optimising
quality and reproducibility of the experiments and by accelerating data mining and analysis.
The Bioinformatics Center (BIC)
Modern research in cancer biology implies the collection of extensive data from experimental models concerning
specific genetic lesions that drive cancer initiation and progression. Such data will include, for example, large
sets of expression transcript profiling, comparative genomic hybridization profiling, whole genome sequencing,
immunohistochemical data, and morphologic data that will be peculiar to each specific tumor. Thus, a
bioinformatics platform for integrated data tracking and normalization is critical to the successful realization
of this endeavor. BIC comprises a web-based bioinformatics platform (Laboratory Assistant Suite, LAS; http://
devircc.polito.it/wordpress/)that assists biomedical researchers in multiple activities, which range from tracking
data generation and execution of standard operating procedures (SOPs) to management of multidimensional
molecular profiles and complex data analysis and integration, by managing multiple independent databases
that are linked together in an interconnected network (‘oncogrid’).
The Oncology Imaging Center (OIC)
Basic research in disciptopics such as cell biology, molecular genetics and developmental biology has
provided invaluable insights into the regulatory circuits that govern cancer onset and progression. Within this
context, we postulate that imaging studies in cell topics and tissues will parallel genomic analyses and in vivo
experimentation, constituting an integrative platform for rapid testing of emerging research directions.
OIC technologies include comprehensive microscopic imaging systems, such as confocal microscopes, live-cell
devices for real-time monitoring of cellular behaviors, and high-throughput platforms for functional screening
The Flow Cytometry Center (FLOCC)
Increasing evidence shows that tumors are structured in a hierarchical form, with a majority of cells undergoing
aberrant differentiation but retaining a proliferative capacity limited over time, and a tiny fraction of cancer
stem cells (CSCs) or cancer-initiating cells (CICs) that are able to self-renew and continuously regenerate or add
to the tumor. FLOCC enables researchers to take advantage of state-of-the-art FACS (fluorescence-activated cell
sorter) technologies and dedicated personnel with highly specialized technical skills in order to tackle these
issues, by allowing analysis and prospective isolation of individual cancer cells within highly heterogeneous
populations. series of human cancer specimens directly transplanted into mice (“xenopatients”).
Team
Piero Alberto, Paola Bernabei, Jadwiga Biela, Michela Buscarino, Daniela Cantarella, Dario Caponi, Giorgio
Corti, Giorgia Migliardi, Francesca Cottino, Alessandro Fiori, Emanuele Geda, Stefania Giove, Alberto Grand,
Barbara Martinoglio, Laura Palmas, Roberta Porporato, Natalia Santoro, Solange Tienga.
The Oncogenomics Center (OGC)
Genetic alterations in tumors are predictors of response or resistance to targeted therapies, and their identification
is mandatory for molecular diagnosis and therapeutic decisions. Technological advances in experimental and
informatics methodologies over the past 10 years have made possible the characterization of cancer genomes.
OGC is the supportive infrastructure for all genomic studies, including transcriptional, mutational and gene copy
number analyses of cells, tissues and liquid biopsies. Dedicated personnel and instrumentation are devoted to
provide services for qRT-PCR studies, Sanger and Next Generation Sequencing experiments, Gene Expression
Array analyses and BEAMing tests.
84 | Core Facilities
Core Facilities | 85
Grant Office and Research Administration
Daniela Gramaglia PhD
E-mail: [email protected]
Phone: +39.011.9933211
The Scientific Director’s Office supervises, coordinates
and manages the basic, translational and clinical scientific research in the Institute. To this end, the Grant Office provides the scientific support for Institute research
Michelina Bruno Ms
E-mail: [email protected]
Phone: + 39.011.9933237
Alessia Gammino Ms
E-mail: [email protected]
Phone: +39.011.9933841
activities and acts as a liaison between researchers and
funding agencies. The Grant Office assists researchers
in identifying appropriate research funding opportunities, centralizing all information on major national and
international, private or public, agencies, foundations, and institutions that support research. Whenever a call
for a research grant is issued, it is advertised throughout the Institute by e-mail. The Grant Office provides assistance to researchers in the preparation of applications, in the drawing up of the budget - together with the
administrative office of the Institute -, in completing the application forms and interpreting the regulations of
the granting agencies, assuring compliance with the sponsors’ policies and requirements.In case of successful
outcome of the proposals, the Grant Office helps in preparing reports, consortium agreements with collaborating institutions, and renewal forms.
Electronic Data Processing Unit
Damion Milne
E-mail: [email protected]
Phone: +39.011.9933985
Giorgio Giardina
E-mail: [email protected]
Phone +39.011.9933086
The EDP unit develops and maintains the Master Data-
Gaetano Lazzarotto
E-mail: [email protected]
funds, human resources and research publication output,
Phone: +39.011.9933887
of the Research units at the Institute. The EDP unit runs
base, a unique tool, developed in-house, which tracks the
the Candiolo Cancer Institute public web site and the Intranet. The unit also provides IT support to the Research
departments and to the Institute’s meetings and conferences. The unit prepares the annual Scientific Report.
86 | Grant Office and Research Administration - EDP
List of Publications | 87
Aglietta M, Barone C, Sawyer MB, Moore MJ, Miller WH Jr, Bagalà C, Colombi F, Cagnazzo C, Gioeni L, Wang E,
List of Publications 2014
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Anto-
Huang B, Fly KD, Leone F.
narakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL,
A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemothe-
Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C,
rapy-naive patients with metastatic pancreatic cancer.
Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K,
Ann Oncol. 25: 1750-5, 2014
Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang
IF: 6.578
CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein
B, Papadopoulos N, Diaz LA Jr.
Ascierto PA, Simeone E, Sileni VC, Del Vecchio M, Marchetti P, Cappellini GC, Ridolfi R, de Rosa F, Cognetti F, Fer-
Detection of circulating tumor DNA in early- and late-stage human malignancies.
raresi V, Testori A, Queirolo P, Bernengo MG, Guida M, Galli L, Mandalà M, Cimminiello C, Rinaldi G, Carnevale-
Sci Transl Med. 6: 224ra24, 2014
Schianca F, Maio M.
IF: 14.414
Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from
theItalian cohort of the ipilimumab expanded access program.
Biglia N, Ponzone R, Bounous VE, Mariani LL, Maggiorotto F, Benevelli C, Liberale V, Ottino MC, Sismondi P.
Cancer Invest. 32: 144-9, 2014
Role of re-excision for positive and close resection margins in patients treated with breast-conserving surgery.
IF: 2.060
Breast. 23: 870-5, 2014
IF: 2.581
Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, Del Vecchio M, Di Guardo L, Marchetti
P, Ridolfi R, Cognetti F, Testori A, Bernengo MG,Guida M, Marconcini R, Mandalà M, Cimminiello C, Rinaldi
Blair BG, Bardelli A, Park BH.
G, Aglietta M, Queirolo P.
Somatic alterations as the basis for resistance to targeted therapies.
Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access
J Pathol. 232: 244-54, 2014
programme cohort.
IF: 7.330
J Transl Med. 12: 116, 2014
IF: 3.991
Bleeker FE, Lamba S, Zanon C, Molenaar RJ, Hulsebos TJ, Troost D, van Tilborg AA, Vandertop WP, Leenstra S,
van Noorden CJ, Bardelli A.
Aversa C, Rossi V, Geuna E, Martinello R, Milani A, Redana S, Valabrega G, Aglietta M, Montemurro F.
Mutational profiling of kinases in glioblastoma.
Metastatic breast cancer subtypes and central nervous system metastases.
BMC Cancer. 14: , 2014
Breast. 23: 623-8, 2014
IF: 3.319
IF: 2.581
Boccaccio C, Comoglio PM.
Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C,
MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure.
Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P,
Curr Opin Cell Biol. 31: 98-105, 2014
Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant
IF: 8.736
Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group (Leone F.).
Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil
Boccaccio C, Luraghi P, Comoglio PM.
and folinic acid for radically resected gastric cancer.
MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal cancer stem cells.
Ann Oncol 25: 1373-8, 2014
Cancer Res. 74: 3647-51, 2014
IF: 6.578
IF: 9.284
Basilico C, Hultberg A, Blanchetot C, de Jonge N, Festjens E, Hanssens V, Osepa SI, De Boeck G, Mira A, Caz-
Bussolino F, Giraudo E, Serini G.
zanti M, Morello V, Dreier T, Saunders M, de Haard H, Michieli P.
Class 3 semaphorin in angiogenesis and lymphangiogenesis
Four individually druggable MET hotspots mediate HGF?driven tumor progression.
Chem Immunol Allergy 99: 71-88, 2014
Journal of Clinical Investigation 124: 3172-86, 2014
IF: 0
IF: 13.765
Caizzi L, Ferrero G, Cutrupi S, Cordero F, Ballaré C, Miano V, Reineri S, Ricci L, Friard O, Testori A, Corà D, CaBertoldo F, Silvestris F, Ibrahim T, Cognetti F, Generali D, Ripamonti CI, Amadori D, Colleoni MA, Conte P, Del
selle M, Di Croce L, De Bortoli M.
Mastro L, De Placido S, Ortega C, Santini D.
Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells.
Targeting bone metastatic cancer: Role of the mTOR pathway.
Proc Natl Acad Sci U S A. 111: 4892-7, 2014
Biochim Biophys Acta. 1845: 248-54, 2014
IF: 9.809
IF: 7.584
88 | List of Publications
List of Publications | 89
Caneparo A, Massucco P, Vaira M, Maina G, Giovale E, Coggiola M, Cinquegrana A, Robella M, De Simone M.
Cremonesi M, Chiesa C, Strigari L, Ferrari M, Botta F, Guerriero F, De Cicco C, Bonomo G, Orsi F, Bodei L, Di Dia
Contamination risk for operators performing semi-closed HIPEC procedure using cisplatin.
A, Grana CM, Orecchia R.
EJSO-Eur J Surg Oncol.40: 925-9, 2014
Radioembolization of hepatic lesions from a radiobiology and dosimetric perspective.
IF: 2.892
Front Oncol. : , 2014
IF: 0
Capobianco M, Piccoli G, Neve Vigotti F, Scapoli P, Deagostini MC, Albera C, Roccatello D, Bertolotto A.
Interferon beta-related nephropathy and interstitial lung disease: a new association and a long-term warning.
Cuzick J, Sestak I, Forbes JF, Dowsett M, Knox J, Cawthorn S, Saunders C, Roche N, Mansel RE, von Minckwitz
Mult Scler. Epub ahead of print, 2014
G, Bonanni B, Palva T, Howell A; IBIS-II investigators (Ponzone R).
IF: 4.863
Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international,
double-blind, randomized placebo-controlled trial.
Carillo V, Cozzarini C, Rancati T, Avuzzi B, Botti A, Borca VC, Cattari G, Civardi F, Esposti CD, Franco P, Girelli
Lancet 388: 1041-8, 2014
G, Maggio A, Muraglia A,Palombarini M, Pierelli A, Pignoli E, Vavassori V, Zeverino M, Valdagni R, Fiorino C.
IF: 39.207
Relationships between bladder dose volume/surface histograms and acute urinary toxicity after radiotherapy forprostate cancer.
DAmbrosio L, Aglietta M, Grignani G.
Radiother Oncol. 111: 100-5, 2014
Anticoagulation for central venous catheters in patients with cancer.
IF: 4.857
N Engl J Med. 371: 1362-3, 2014
IF: 54.420
Casale FP, Giurato G, Nassa G, Armond JW, Oates CJ, Corá D, Gamba A, Mukherjee S, Weisz A, Nicodemi M.
Single-cell states in the estrogen response of breast cancer cell lines.
De Luca S, Passera R, Bollito E, Manfredi M, Scarpa RM, Sottile A, Randone DF, Porpiglia F.
PLoS One. 9: e88485, 2014
Comparison of prostate cancer gene 3 score, prostate health index and percentage free prostate-specific anti-
IF: 3.534
gen for differentiating histological inflammation from prostate cancer and other non-neoplastic alterations of
the prostate at initial biopsy.
Chiarion-Sileni V, Pigozzo J, Ascierto PA, Simeone E, Maio M, Calabra L, Marchetti P, De Galitiis F, Testori A,
Anticancer Res 34: 7159-65, 2014
Ferrucci PF, Queirolo P, Spagnolo F, Quaglino P, Carnevale Schianca F, Mandala M, Di Guardo L, Del Vecchio M.
IF: 1.872
Ipilimumab retreatment in patients with pretreated advanced melanoma:
the expanded access programme in Italy.
Diaz LA Jr, Bardelli A.
Br J Cancer. 110: 1721-6, 2014
Liquid biopsies: genotyping circulating tumor DNA.
IF: 4.817
J Clin Oncol. 32: 579-86, 2014
IF: 17.960
Coppola F, Regge D, Flor N, Papadopoulos D, Golfieri R.
Flat lesions missed at conventional colonoscopy (CC) and visualized by CT colonography (CTC): a pictorial essay.
Evangelista L, Redana S, Racca M, Geuna E, Vinante L, Zago G, De Carolis V, Ghiotto C, Saladini G, Varetto T
Abdom Imaging 39: 25-32, 2014
FDG avidity at PET/CT during adjuvant hormonal therapy in patients with breast cancer.
IF: 1.730
Clin Nucl Med. 39: e135-41, 2014
IF: 2.857
Corà D, Astanina E, Giraudo E, Bussolino F.
Semaphorins in cardiovascular medicine.
Fornaro L, Cereda S, Aprile G, Di Girolamo S, Santini D, Silvestris N, Lonardi S, Leone F, Milella M, Vivaldi C,
Trends Mol Med. 20: 589-598, 2014
Belli C, Bergamo F, Lutrino SE, Filippi R, Russano M, Vaccaro V, Brunetti AE, Rotella V, Falcone A, Barbera MA,
IF: 10.110
Corbelli J, Fasola G, et al.
Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.
Corso S, Giordano S.
Br J Cancer. 110: 2165-9, 2014
Targeted therapies in cancer and mechanisms of resistance.
IF: 4.817
J Mol Med (Berl) 92: 677-9, 2014
IF: 4.739
Gagliardi PA, di Blasio L, Puliafito A, Seano G, Sessa R, Chianale F, Leung T, Bussolino F, Primo L.
PDK1-mediated activation of MRCK
J Cell Biol. 206: 415-34, 2014
IF: 9.786
90 | List of Publications
List of Publications | 91
Gallo S, Gatti S, Sala V, Albano R, Costelli P, Casanova E, Comoglio PM, Crepaldi T.
Iussich G, Correale L, Senore C, Hassan C, Segnan N, Campanella D, Bert A, Galatola G, Laudi C, Regge D.
Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis
Computer-aided detection for computed tomographic colonography screening: a prospective comparison of
and autophagy.
a double-reading paradigm with first-reader computer-aided detection against second-reader computer-aided
Cell Death Dis. 5: e1185, 2014
detection.
IF: 5.177
Invest Radiol. 49: 173-82, 2014
IF: 4.453
Gammaitoni L, Leuci V, Mesiano G, Giraudo L, Todorovic M, Carnevale-Schianca F, Aglietta M, Sangiolo D.
Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective.
Katsila T, Juliachs M, Gregori J, Macarulla T, Villarreal L, Bardelli A, Torrance C, Elez ME, Tabernero J, Villanueva J.
Expert Opin Biol Ther. 14: 1259-70, 2014
Circulating pEGFR is a Candidate Response Biomarker of Cetuximab Therapy in Colorectal Cancer.
IF: 3.653
Clin Cancer Res. 20: 6346-56, 2014
IF: 8.193
Garibaldi E, Cattari G, Delmastro E, Siatis D, Racca M, Maggio A, Gabriele D, Frangipane E, Gabriele P.
Technical and clinical description of a case of extensive anogenital Paget’s disease associated with anal cancer
Lamba S, Russo M, Sun C, Lazzari L, Cancelliere C, Grernrum W, Lieftink C, Bernards R, Di Nicolantonio F, Bardelli A.
treated by tomotherapy.
RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells.
Tumori 100: e41-4, 2014
Cell Rep. 8: 1475-83, 2014
IF: 1.090
IF: 7.207
Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio PM.
Leto SM, Trusolino L.
The ROR1 pseudokinase diversifies signaling outputs in MET-addicted cancer cells.
Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies.
Int J Cancer. 135: 2305-16, 2014
J Mol Med (Berl). 92: 709-22, 2014
IF: 5.007
IF: 4.739
Giacobini P, Parkash J, Campagne C, Messina A, Casoni F, Vanacker C, Langlet F, Hobo B, Cagnoni G, Gallet S,
Lupo B, Trusolino L.
Hanchate NK, Mazur D, Taniguchi M, Mazzone M, Verhaagen J, Ciofi P, Bouret SG, Tamagnone L, Prevot V.
Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited.
Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.
Biochim Biophys Acta. 1846: 201-15, 2014
PLoS Biol. 12: e1001808, 2014
IF: 7.584
IF: 11.771
Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM 3rd, PeGronchi A, De Paoli A, Dani C, Merlo DF, Quagliuolo V, Grignani G, Bertola G, Navarria P, Sangalli C, Buonadonna
rera T, Bertotti A, Trusolino L, Comoglio PM, Boccaccio C.
A, De Sanctis R, Sanfilippo R, Dei Tos AP, Stacchiotti S, Giorello L, Fiore M, Bruzzi P, Casali PG.
MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.
Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: a phase I-II study from the Italian
Cancer Res. 74: 1857-69, 2014
Sarcoma Group.
IF: 9.284
Eur J Cancer. 50: 784-92, 2014
IF: 4.819
Luvero D, Milani A, Ledermann JA.
Treatment options in recurrent ovarian cancer: latest evidence and clinical potential.
Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Malandsmo
Ther Adv Med Oncol. 6: 229-39, 2014
GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A.
IF: 0
Patient-derived xenograft models: an emerging platform for translational cancer research.
Cancer Discov. 4: 998-1013, 2014
Luzzati F, Nato G, Oboti L, Vigna E, Rolando C, Armentano M, Bonfanti L, Fasolo A, Peretto P.
IF: 15.929
Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons.
Development. 141: 4065-75, 2014
Hobor S, Van Emburgh BO, Crowley E, Misale S, Di Nicolantonio F, Bardelli A.
IF: 6.273
TGF-a and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells.
Clin Cancer Res. 20: 6429-38, 2014
Magro G, Righi A, Caltabiano R, Casorzo L, Michal M.
IF: 8.193
Vulvovaginal angiomyofibroblastomas: morphologic, immunohistochemical, and fluorescence in situ hybridization analysis for deletion of 13q14 region.
Hum Pathol. 45: 1647-55, 2014
IF: 2.806
92 | List of Publications
List of Publications | 93
Marino D, Leone F, DAvanzo F, Ribero D, Capussotti L, Aglietta M.
Montemurro F, Di Cosimo S.
Potentially resectable metastatic colorectal cancer: An individualized approach to conversion therapy.
Pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy.
Crit Rev Oncol Hematol. 92: 218-26, 2014
Breast. 23: 690-1, 2014
IF: 4.046
IF: 2.581
Martin V, Corso S, Comoglio PM, Giordano S.
Moreno García V, Olmos D, Gomez-Roca C, Cassier PA, Morales-Barrera R, Del Conte G, Gallerani E, Brunetto
Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug
AT, Schöffski P, Marsoni S, Schellens JH, Penel N, Voest E, Evans J, Plummer R, Wilson RH, Soria JC, Tabernero
dependence.
J, Verweij J, Kaye SB.
Mol Oncol. 8: 1561-74, 2014
Dose-Response Relationship in Phase I Clinical Trials: A European Drug Development Network (EDDN) Collabo-
IF: 5.935
ration Study.
Clin Cancer Res. 20: 5663-71, 2014
Mesiano G, Leuci V, Giraudo L, Gammaitoni L, Carnevale Schianca F, Cangemi M, Rotolo R, Capellero S, Pigno-
IF: 8.193
chino Y, Grignani G, Aglietta M, Sangiolo D.
Adoptive immunotherapy against sarcomas.
Muratore A, Mellano A, Tarantino G, Marsanic P, De Simone M, Di Benedetto F.
Expert Opin Biol Ther. 0: , 2014
Radiofrequency vessel-sealing system versus the clamp-crushing technique in liver transection: results of a
IF: 3.653
prospective randomized study on 100 consecutive patients.
HPB (Oxford). 16: 707-12, 2014
Milani A, Geuna E, Mittica G, Valabrega G.
IF: 2.050
Overcoming endocrine resistance in metastatic breast cancer: Current evidence and future directions
World J Clin Oncol. 5: 990-1001, 2014
Musiani D, Hammond DE, Cirillo L, Erriquez J, Olivero M, Clague MJ, Di Renzo MF.
IF: 0
PIM2 Kinase Is Induced by Cisplatin in Ovarian Cancer Cells and Limits Drug Efficacy.
J Proteome Res. 7: 4970-82, 2014
Milani A, Sangiolo D, Aglietta M, Valabrega G.
IF: 5.001
Recent advances in the development of breast cancer vaccines.
Breast Cancer (Dove Med Press). 6: 159-68, 2014
Musiani D, Konda JD, Pavan S, Torchiaro E, Sassi F, Noghero A, Erriquez J, Perera T, Olivero M, Di Renzo MF.
IF: 0
Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to
MET-targeted therapy.
Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, Russo M, Buscarino M, Lazzari L, Sartore-Bianchi
FASEB J. 0: , 2014
A, Bencardino K, Amatu A, Lauricella C, Valtorta E, Siena S, Di Nicolantonio F, Bardelli A.
IF: 5.480
Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.
Necchi A, Pennati M, Zaffaroni N, Landoni E, Giannatempo P, Raggi D, Schwartz LH, Morosi C, Crippa F, Fara E,
Sci Transl Med. 6: 224ra26, 2014
Nicolai N, Lanocita R, Sava T, Sacco C, Messina C, Ortega C, De Braud FG, Salvioni R, Daidone MG, Gianni AM,
IF: 14.414
Mariani L.
Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pa-
Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A.
zopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy.
Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution.
Br J Cancer. 110: 26-33, 2014
Cancer Discov. 4: 1269-80, 2014
IF: 4.817
IF: 15.929
Olivero M, Dettori D, Arena S, Zecchin D, Lantelme E, Di Renzo MF.
Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, Wesseling P, Hulsebos TJ, Troost
The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase.
D, van Tilborg AA, Leenstra S, Vandertop WP, Bardelli A, van Noorden CJ, Bleeker FE.
Oncotarget. 5: 5992-6002, 2014
The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than
IF: 6.627
either IDH1 or MGMT alone.
Neuro Oncol. 16: 1263-73, 2014
Osella M, Riba A, Testori A, Corà D, Caselle M.
IF: 5.286
Interplay of microRNA and epigenetic regulation in the human regulatory network.
Front Genet. 5: 345, 2014
IF: 0
94 | List of Publications
List of Publications | 95
Parri M, Pietrovito L, Grandi A, Campagnoli S, De Camilli E, Bianchini F, Marchiò S, Bussolino F, Jin B, Sarmien-
Porpiglia F, Russo F, Manfredi M, Mele F, Fiori C, Bollito E, Papotti M, Molineris I, Passera R, Regge D.
tos P, Grandi G, Viale G, Pileri P, Chiarugi P, Grifantini R.
The Roles of Multiparametric Magnetic Resonance Imaging, PCA3 and Prostate Health Index-Which is the Best
Angiopoietin-like 7, a novel pro-angiogenetic factor over-expressed in cancer.
Predictor of Prostate Cancer after a Negative Biopsy?
Angiogenesis 17: 881-96, 2014
J Urol. 192: 60-6, 2014
IF: 4.410
IF: 3.753
Pastò A, Serafin V, Pilotto G, Lago C, Bellio C, Trusolino L, Bertotti A, Hoey T, Plateroti M, Esposito G, Pinazza
Regge D, Iussich G, Senore C, Correale L, Hassan C, Bert A, Montemezzi S, Segnan N.
M, Agostini M, Nitti D, Amadori A, Indraccolo S.
Population screening for colorectal cancer by flexible sigmoidoscopy or CT colonography: study protocol for a
NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells.
multicenter randomized trial.
Cancer Res. 74: 2106-18, 2014
Trials 28: , 2014
IF: 9.284
IF: 2.117
Pavesi A, Soncini M, Zamperone A, Pietronave S, Medico E, Redaelli A, Prat M, Fiore GB.
Righi A, Sarotto I, Casorzo L, Cavalchini S, Frangipane E, Risio M.
Electrical conditioning of adipose-derived stem cells in a multi-chamber culture platform.
Tumour budding is associated with hypoxia at the advancing front of colorectal cancer
Biotechnol Bioeng. 111: 1452-63, 2014
Histopathology 0: , 2014
IF: 4.164
IF: 3.301
Pegurri L, Buglione M, Girelli G, Guarnieri A, Meattini I, Ricardi U, Mangoni M, Gabriele P, Bellavita R, Krengli M,
Robella M, Vaira M, Marsanic P, Mellano A, Borsano A, Cinquegrana A, Sottile A, De Simone M.
Bonetta A, Cagna E, Bunkheila F, Borghesi S, Signor M, Di Marco A, Bertoni F, Stefanacci M, Gatta R, De Bari
Treatment of peritoneal carcinomatosis from ovarian cancer by surgical cytoreduction and hyperthermic intra-
B, Magrini SM.
peritoneal chemotherapy (HIPEC).
Changes in patterns of practice for prostate cancer radiotherapy in Italy 1995-2003. A survey of the Prostate
Minerva Chir. 69: 27-35, 2014
Cancer Study Group of the Italian Radiation Oncology Society.
IF: 0.707
Tumori 100: 42216, 2014
IF: 1.090
Robella M, Vaira M, Mellano A, Marsanic P, Cinquegrana A, Borsano A, Barbera M, Caneparo A, Siatis D, Sottile
A, De Simone M.
Pennacchietti S, Cazzanti M, Bertotti A, Rideout WM 3rd, Han M, Gyuris J, Perera T, Comoglio PM, Trusolino L, Michieli P.
Treatment of diffuse malignant peritoneal mesothelioma (DMPM) by cytoreductive surgery and HIPEC.
Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs.
Minerva Chir. 69: 42248, 2014
Cancer Res. 74: 6598-609, 2014
IF: 0.707
IF: 9.284
Rocci A, Gambella M, Aschero S, Baldi I, Trusolino L, Cavallo F, Gay F, Larocca A, Magarotto V, Omedè P, Isaia
Peraldo Neia C, Cavalloni G, Balsamo A, Venesio T, Napoli F, Sassi F, Martin V, Frattini M, Aglietta M, Leone F.
G, Bertotti A, Liberati AM, Catalano L, De Rosa L, Musto P, Vallone R, Falcone A, Drandi D, Ladetto M, Comoglio
Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR.
PM, Boccadoro M, Palumbo A.
Genes Chromosomes Cancer 53: 1033-40, 2014
MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients.
IF: 3.836
Br J Haematol. 164: 841-50., 2014
IF: 4.959
Peraldo-Neia C, Cavalloni G, Soster M, Gammaitoni L, Marchiò S, Sassi F, Trusolino L, Bertotti A, Medico E,
Capussotti L, Aglietta M, Leone F.
Rolland Y, Marighetti P, Malinverno C, Confalonieri S, Luise C, Ducano N, Palamidessi A, Bisi S, Kajiho H, Troglio
Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.
F, Shcherbakova OG, Dunn AR, Oldani A, Lanzetti L, Di Fiore PP, Disanza A, Scita G.
BMC Cancer 5: 918, 2014
The CDC42-interacting protein 4 controls epithelial cell cohesion and tumor dissemination.
IF: 3.319
Dev Cell. 30: 553-68, 2014
IF: 10.366
Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L, Angioni MM, Raschioni C, Testore E, Roncalli M, Giordano S, Columbano A.
Rossi V, Martinello R, Aversa C, Montemurro F.
YAP activation is an early event and a potential therapeutic target in liver cancer development.
2013 San Antonio Breast Cancer Symposium.
J Hepatol. 61: 1088-96, 2014
Expert Opin Pharmacother. 15: 1191-5, 2014
IF: 10.401
IF: 3.085
96 | List of Publications
List of Publications | 97
Russo M, Di Nicolantonio F, Bardelli A.
Sini V, Lunardi G, Cirillo M, Turazza M, Bighin C, Giraudi S, Levaggi A, Piccioli P, Bisagni G, Gnoni R, Stridi G,
Climbing RAS, the everest of oncogenes.
Porpiglia M, Picardo E, Ponzone R, Marenco D, Mansutti M, Puglisi F, Del Mastro L.
Cancer Discov. 4: 19-21, 2014
Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole.
IF: 15.929
Br J Cancer. 110: 1133-8, 2014
IF: 4.817
Samarelli AV, Riccitelli E, Bizzozero L, Silveira TN, Seano G, Pergolizzi M, Vitagliano G, Cascone I, Carpentier G,
Bottos A, Primo L, Bussolino F, Arese M.
Siravegna G, Bardelli A.
Neuroligin 1 induces blood vessel maturation by cooperating with the
Minimal residual disease in breast cancer: in blood veritas.
J Biol Chem. 289: 19466-76, 2014
Clin Cancer Res. 20: 2505-7, 2014
IF: 4.600
IF: 8.193
Sangiolo D, Mesiano G, Gammaitoni L, Aglietta M, Grignani G.
Siravegna G, Bardelli A.
Activity of cytokine-induced killer cells against bone and soft tissue sarcoma.
Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance.
Oncoimmunology. 3: e28269, 2014
Genome Biol. 15: 449, 2014
IF: 6.283
IF: 10.500
Scalabrini DR, Caravelli D, Schianca FC, DAmbrosio L, Tolomeo F, Boccone P, Manca A, De Rosa G, Nuzzo A,
Spaccarotella E, Pellegrino E, Ferracin M, Ferreri C, Cuccuru G, Liu C, Iqbal J, Cantarella D, Taulli R, Provero P, Di
Aglietta M, Grignani G.
Cunto F, Medico E, Negrini M, Chan WC,Inghirami G, Piva R.
Complete remission of paraneoplastic vanishing bile duct syndrome after the successful treatment of Hodgkin’s
STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive
lymphoma: a case report and review of the literature.
anaplastic large cell lymphoma.
BMC Res Notes. 7: 529, 2014
Haematologica. 99: 116-24, 2014
IF: 0
IF: 5.868
Sciandra M, Marino MT, Manara MC, Guerzoni C, Grano M, Oranger A, Lucarelli E, Lollini PL, Dozza B, Pratelli
Spada C, Stoker J, Alarcon O, Barbaro F, Bellini D, Bretthauer M, De Haan MC, Dumonceau JM, Ferlitsch M, Hal-
L, Di Renzo MF, Colombo MP, Picci P, Scotlandi K.
ligan S, Helbren E, Hellstrom M, Kuipers EJ, Lefere P, Mang T, Neri E, Petruzziello L, Plumb A, Regge D, Taylor
CD99 drives terminal differentiation of osteosarcoma cells by acting as a spatial regulator of ERK 1/2.
SA, Hassan C, Laghi A.
J. Bone Miner Res. 29: 1295-309, 2014
Clinical indications for computed tomographic colonography: European Society of Gastrointestinal Endoscopy
IF: 6.589
(ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline.
Endoscopy 46: 897-915., 2014
Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Puliafito A, Bouvard C, Sessa R, Tarone G, Sorokin L, Helley D,
IF: 5.196
Jain RK, Serini G, Bussolino F, Primo L.
Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis.
Stacchiotti S, Tortoreto M, Baldi GG, Grignani G, Toss A, Badalamenti G, Cominetti D, Morosi C, Dei Tos AP,
Nat Cell Biol. 16: 931-41, 2014
Festinese F, Fumagalli E, Provenzano S, Gronchi A, Pennacchioli E, Negri T, Dagrada GP, Spagnuolo RD, Pilotti
IF: 20.058
S, Casali PG, Zaffaroni N.
Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour.
Seano G, Daubon T, Gacnot E, Primo L.
Eur J Cancer. 50: 3021-8, 2014
Podosomes as novel players in endothelial biology.
IF: 4.819
Eur J Cell Biol. 93: 405-12, 2014
IF: 3.699
Stella GM, Inghilleri S, Pignochino Y, Zorzetto M, Oggionni T, Morbini P, Luisetti M.
Activation of Oncogenic Pathways in Idiopathic Pulmonary Fibrosis.
Silvestri I, Testa F, Zappasodi R, Cairo CW, Zhang Y, Lupo B, Galli R, Di Nicola M, Venerando B, Tringali C.
Transl Oncol. 7: 650-5, 2014
Sialidase NEU4 is involved in glioblastoma stem cell survival.
IF: 2.558
Cell Death Dis. 5: e1381, 2014
IF: 5.177
98 | List of Publications
List of Publications | 99
Sun C, Hobor S, Bertotti A, Zecchin D, Huang S, Galimi F, Cottino F, Prahallad A, Grernrum W, Tzani A, Schlicker
Vigna E, Comoglio PM.
A, Wessels LF, Smit EF, Thunnissen E, Halonen P, Lieftink C, Beijersbergen RL, Di Nicolantonio F, Bardelli A,
Targeting the oncogenic Met receptor by antibodies and gene therapy.
Trusolino L, Bernards R.
Oncogene 0: , 2014
Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction
IF: 8.559
of ERBB3.
Cell Rep. 7: 86-93, 2014
Vignati A, Giannini V, Carbonaro LA, Bertotto I, Martincich L, Sardanelli F, Regge D.
IF: 7.207
A new algorithm for automatic vascular mapping of DCE-MRI of the breast: Clinical application of a potential
new biomarker.
Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zec-
Comput Methods Programs Biomed. 117: 482-8, 2014
chin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF,
IF: 1.093
Beijersbergen RL, Bardelli A, et al.
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.
Vivaldi C, Fornaro L, Cereda S, Aprile G, Santini D, Silvestris N, Lonardi S, Leone F, Milella M, Brandi G, Vasile E.
Nature. 508: 118-22, 2014
Second-line chemotherapy in advanced biliary cancer: the present now will later be past.
IF: 42.351
Ann Oncol. 25: 2443-4, 2014
IF: 6.578
Vaira M, Robella M, Mellano A, Sottile A, De Simone M.
Iterative procedures combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated peritoneal recurrence.
Int J Hyperthermia. 30: 565-9, 2014
IF: 2.769
Valetti S, Maione F, Mura S, Stella B, Desmaële D, Noiray M, Vergnaud J, Vauthier C, Cattel L, Giraudo E, Couvreur P.
Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor.
J Control Release. 192: 29-39, 2014
IF: 7.261
Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, Siena S, Bardelli A.
Acquired resistance to EGFR-targeted therapies in
Mol Oncol. 8: 1084-94, 2014
IF: 5.935
Van Schaeybroeck S, Kalimutho M, Dunne PD, Carson R, Allen W, Jithesh PV, Redmond KL, Sasazuki T, Shirasawa S, Blayney J, Michieli P, Fenning C, Lenz HJ, Lawler M, Longley DB, Johnston PG.
ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal
cancer.
Cell Rep. 7: 1940-55, 2014
IF: 7.207
Varetto T, Costa DC.
Ideas from the second UEMS conference on CME/CPD: new EU directives on a patients’ rights in cross-border
healthcare and professional qualifications.
Eur J Nucl Med Mol Imaging. 41: 2169-73, 2014
IF: 5.217
100 | List of Publications
List of Publications | 101