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Program Director/Principal Investigator (Last, First, Middle):
Kirken, Robert A.
BIOGRAPHICAL SKETCH
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NAME
POSITION TITLE
Francia, Giulio
Assistant Professor
eRA COMMONS USER NAME (credential, e.g., agency login)
FRANCIAG
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
University of Bristol, United Kingdom
ICRF-King’s College London, United Kingdom
University of Toronto, Canada
B.Sc.(1st
Class
Honors)
Ph.D.
Postdoctoral
1991-1994
Biochemistry
1994-1998
1998-2011
Cancer Biology
Cancer Biology
A. Personal Statement (including developmental objectives and plans)
I began my career by starting my PhD at the Imperial Cancer Research Fund in London, UK, which has
since evolved into Cancer UK. I chose to study the process by which tumors spread, or metastasis, that had
fascinated me as an undergraduate, and I began my research career by seeking for new genes whose
expression changes as tumors become more metastatic. After my PhD, I trained as a post-doc in Toronto,
Canada, on aspects of metastasis, therapies for metastatic disease, and tumor resistance to therapy. I now
plan to set up a research program that is internationally recognized for pioneering new ideas, and for
generating models to help translate laboratory findings into the clinic - by developing new metastatic tumor
models, and by refining those I have already established. I have developed the first model of spontaneously
metastatic Her-2 positive breast cancer that can be monitored as mice bearing the disease are treated with
clinically relevant anti-Her-2 strategies (Francia et al MCT 2008, and CCR 2009). The impact of this work has
subsequently led to three editorials (Francia et al Cancer Cell 2009, Nat Rev Cancer 2011, and Francia and
Kerbel Nat. Biotech 2010) where I put forward the hypothesis that testing laboratory models of metastatic
disease is essential to identify mechanisms by which tumors respond to current therapies in the clinic, and by
which they develop resistance to current treatments. I now want to test my hypothesis by developing two new
models of human breast cancer that endogenously over-express Her-2, One such model, termed BT474V3, I
have now selected for spontaneous metastatic capacity in immunodeficient mice.
The research I propose to carry out is central to the further development of my academic career. The
generation of new preclinical models of spontaneously metastatic breast cancer will allow me to establish
collaborations (as has been the case with the models I have thus far generated), with basic researchers,
translational cancer researchers (i.e. surgeons, oncologists and pathologists), as well as with industry –
namely those companies interested in the use of advanced disease models to test investigational new drugs.
Thus, for example, current collaborations include those with researchers interested in tumor imaging, in the
use of ultrasound to facilitate the delivery of tumor targeting drugs to metastatic deposits in the brain, and in
the in vivo evaluation of a new small molecule inhibitor of Her-2 for the treatment of Her-2 positive breast
cancer. These scientific interactions will be important to establish my credentials, and my reputation, as an
established investigator in the field of experimental therapeutics for metastatic breast cancer.
The new Her-2 positive models will also produce a number of publications in peer-reviewed journals, as
well as opportunities to present the work at scientific meetings, in which my lab will describe the development
of the models, or their application to identify new therapeutic concepts, or their use to uncover mechanisms by
which tumors develop resistance to current therapies. The collaborations initiated, the scientific presentations
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Program Director/Principal Investigator (Last, First, Middle):
Kirken, Robert A.
at meetings, and the manuscript published, will altogether form an important part of my successful application
for tenure at UTEP. They will also be critical in allowing me to seek additional funding; that will ensure that I
can place my program at the forefront of our research to understand how metastases emerge and develop,
and to the identification of new therapies for metastatic breast cancer.
This SC1 proposal builds on exciting recent results and proposes to develop additional models of Her-2
breast cancer to include tumors from the Hispanic population (which is not represented in the available panel
of Her-2 positive breast cancer cell lines). We will use the new models, together with those already developed,
to both optimize chemotherapy regimens and Her-2 targeting strategies, since current clinical protocols
combine chemotherapy with anti-Her-2 drugs to treat metastatic disease. I have the necessary expertise to
complete the work proposed. In addition, to assist me I have sought the collaboration of Dr. Mark Uhlik of Eli
Lilly and Company, who will continue to make available a new oral gemcitabine. This drug has produced
promising anti-tumor responses in my ongoing experiments, and it is currently being evaluated in clinical trials.
With regards to publications, I plan to submit a manuscript on the two new Her-2 models I have derived by the
beginning of year 2 of the proposal. The development of cell lines from fresh patient tumors from the El Paso
region will be published in year 3 of this proposal, and 2 more peer reviewed publications will be submitted by
year 4. Those will deal with the response of the new models to Her-2 targeting therapy, the mechanisms by
which the models can become drug resistant, and on new protocols that should be evaluated in clinical trials
for the treatment of Her-2 positive breast cancer. The data gathered will be used to submit for an NIH R01
grant by year 4 of this proposal.
B. Positions, Honors
Positions and Employment
1994-1998
PhD Student, Imperial Cancer Research Fund, King’s College London, London, United Kingdom.
1998-2011
Post-doctoral Fellow, Sunnybrook Research Institute, University of Toronto, Canada.
Jan 2012Tenure-Track Assistant Professor, Department of Biological Sciences, University of Texas at El
Paso, El Paso, TX
Other Experience and Professional Memberships
2003-present Associate Member, American Association for Cancer Research
Honors:
1994-1998
1998-2001
2003
2004
2012
2012
Imperial Cancer Research Fund (ICRF) Studentship
Sunnybrook Health Sciences Centre Post-Doctoral Fellowship, Canada.
AACR-AstraZeneca Scholar-in-Training Award-2003 AACR Annual Meeting,
Washington, D.C.
AACR-AFLAC Scholar-in-Training Award-2004 AACR Special Conference
“Chromatin, Chromosomes and Cancer Epigenetics” Waikoloa, Hawaii, Nov 10-14.
2012 ASCB MAC Junior Faculty and Postdoctoral Fellows Career Development Workshop
Travel Award
NIH Early Career Reviewer, Tumor Progression and Metastasis study section
C. Selected Peer-reviewed Publications
Most relevant to the current application
1. Francia G, Emmenegger U, Lee CR, Shaked Y, Folkins C, Mossoba M, Medin JA, Man S, Zhu Z, Witte L,
Kerbel RS. Long-term progression and therapeutic response of visceral metastatic disease non-invasively
monitored in mouse urine using beta-human choriogonadotropin secreting tumor cell lines. Mol Cancer
Ther. 2008 Oct;7(10):3452-9.
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2. Francia G, Man S, Lee CJ, Lee CR, Xu P, Mossoba ME, Emmenegger U, Medin JA, Kerbel RS.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer
xenografts. Clin Cancer Res. 2009 Oct 15;15(20):6358-66.
3. Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS. Mouse models of advanced spontaneous metastasis
for experimental therapeutics. Nat Rev Cancer. 2011 Feb;11(2):135-41.
4. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel
RS. Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer
xenografts. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):904-16.
5. Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a mediator of the antiangiogenic
effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12917-22.
Additional publications of importance to the fields of metastasis and cancer therapeutics
1. Francia G, Poulsom R, Hanby AM, Mitchell SD, Williams G, Mckee P, Hart IR.Identification by differential
display of a protein phosphatase-2A regulatory subunit preferentially expressed in malignant melanoma
cells. Int J Cancer. 1999. Aug 27;82(5):709-13.
2. Mutsaers AJ, Francia G, Man S, Lee CR, Ebos JM, Wu Y, Witte L, Berry S, Moore M, Kerbel RS. Dosedependent increases in circulating TGF-alpha and other EGFR ligands act as pharmacodynamic markers
for optimal biological dosing of cetuximab and are tumor independent. Clin Cancer Res. 2009 Apr
1;15(7):2397-405. Epub 2009 Mar 1
3. Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS. Highly efficacious nontoxic preclinical
treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide
metronomic chemotherapy. Cancer Res. 2006 Apr 1;66(7):3386-91.
4. Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS.
Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through
the drinking water. Cancer Res. 2002 May 15;62(10):2731-5.
5. Francia G, Kerbel RS. Raising the bar for cancer therapy models. Nat Biotechnol. 2010 Jun;28(6):561-2.
Additional selected peer-reviewed publications (Selected from 31 peer-reviewed research papers, in
chronological order)
1. Francia G, Man S, Teicher B, Grasso L, Kerbel RS. Gene expression analysis of tumor spheroids reveals a
role for suppressed DNA mismatch repair in multicellular resistance to alkylating agents. Mol Cell Biol.
2004 Aug;24(15):6837-49.
2. Shaked Y, Emmenegger U, Francia G, Chen L, Lee CR, Man S, Paraghamian A, Ben-David Y, Kerbel
RS.Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective longterm chemotherapy treatment strategy. Cancer Res. 2005 Aug 15;65(16):7045-51.
3. Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS. Low-dose
metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with
enhanced efficacy that exploits tumor hypoxia. Cancer Res. 2006 Feb 1;66(3):1664-74.
4. Francia G, Emmenegger U, Kerbel RS. Tumor-associated fibroblasts as "Trojan Horse" mediators of
resistance to anti-VEGF therapy. Cancer Cell. 2009 Jan 6;15(1):3-5.
5. Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S, Kerbel RS. Tumors that acquire resistance
to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose
cyclophosphamide. Neoplasia. 2011 Jan;13(1):40-8.
D. Research Support
Other Support
UTEP Startup funding (Total = $ 256,000)
Francia (PI) 1/1/12 – 1/1/14
Development of new preclinical metastasis models to study cancer therapeutics
The goal of this project is to develop new models of metastatic human cancer in mice, and to use those models
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Program Director/Principal Investigator (Last, First, Middle):
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to identify new anti-cancer treatments.
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