Download Saturday 30 April - R. Stahel - Biology of cancer

Principles of Cancer Biology
and Therapy
Prof Dr Solange Peters, MD, PhD
Cancer Center
Lausanne
Switzerland
Cancer is an umbrella term covering a plethora of
conditions characterized by unscheduled and
uncontrolled cellular proliferation
• Almost any mammalian organ and cell type can succumb
to oncogenic transformation
• The causes of cancer are many and varied, and include
genetic predisposition, environmental influences,
infectious agents and ageing
• Transformation occurs by derailing a wide spectrum of
effector pathways. Cancer complexity is what hampered
the development of effective and specific cancer therapies
Cancer and Age
Breast
ALL
Colon
Testicular
CNS
NCCC 1988 - 2004
Cancer is a disease of extraordinary diversity
In terms of
•
cell types of origin
•
organ sites
Nomenclature
• Benign
– “Polyp”
• Malignant
– Epithelial
• Carcinoma
– Mesenchyme
• Sarcoma
– Hematopoietic
• Leukemia
• Lymphoma
• Myeloma
Cancer is a disease of extraordinary diversity
In terms of
•cell types of origin
•organ sites
•etiology
Etiology
• Systemic predisposition
– Inherited cancer syndromes
• p53, BRCA1 and 2, MMR
– Immune deficiency syndromes
• Inherited/Congenital or acquired
• Exposure
– Radiation (cosmic, fallout, radon)
– Chemotherapy (MDS)
– Viruses and bacteria
• EBV, HTLV-I/II, HIV, H. pylori
– Repeated injury (Acid reflux, hepatitis)
•
We show that the lifetime risk of cancers of many different types is
strongly correlated (0.81) with the total number of divisions of the
normal self-renewing cells maintaining that tissue’s homeostasis.
•
These results suggest that only a third of the variation in cancer risk
among tissues is attributable to environmental factors or inherited
predispositions. The majority is due to bad luck (…).
Tomassetti&Vogelstein,Science2015
Mutationsfrequencyvariesaccordingto
cancertype
Comprehensive catalogue of cancer genes throgh somatic point mutations in exome
sequences from 4,742 human cancers and their matched normal-tissue samples
across 21 cancer types
LawrenceMS,etal.Nature.2013.
Melanomasandlung tumorsdisplaymany
moremutationsthanaverage,with~200
nonsynonymous
mutationspertumor.
Theselargernumbers reflecttheinvolvement
ofpotentmutagens.Accordingly, lung cancers
fromsmokers have10timesasmanysomatic
mutationsasthosefrom nonsmokers.
Vogelstein,Science2013
Karyotypedifferencesbetweenanormal
andcancercell
Everycancergenomeisuniquely
alteredfromitshostnormalgenome
“Happyfamiliesareallalike;everyunhappy
familyisunhappyinitsownway”.
LeoTolstoy,AnnaKarenina
Normalhumangenomesareall(mostly)alike;every
cancergenomeisabnormalinitsownway.
Eachcancergenomehasauniquesetofgenome
alterationsfromitsnormalhost
Thesealterations,however,arenotrandombutactin
commonpathwaysandmechanisms
MattMeyerson
WE have been studying “oncogenes”
• Oncogenes
– myc, ras, src, abl, bcl2
• Tumor suppressor genes
– p53, Rb, APC, MEN1, NF1
• MicroRNA
– Transcriptome control
The paradigm of drivers alterations:
lung adenocarcinoma
Definition of drivers?
Inducible expression of mutated HER2 (HER2YVMA):
Rapid development/maintenance of adenosquamous lung
tumors in mice
Cre-mediated activation in lung indicate that (V600E)BRAF mutation can drive
tumour initiation and that its primary effect is to induce high levels of cyclin D1mediated cell proliferation
Perera, PNAS 2009
Who to molecularely assess by
targeted testing, evidence-based?
•
NSCLC adeno
EGFRm, ALKr, RETr, ROSr, HER2m, HER2a, BRAFm; METm, METa
•
Melanoma
BRAFm, (NRASm, KITm (a)?)
•
Colorectal
KRASm, NRASm, BRAFm
•
GIST
KITm, PDGFRαm
•
Glioblastoma:
MGMTmethyl
•
Breast:
HER2a, ERe, PRe
•
Dermatofibrosarcoma:
PDGFRβr
•
Stomach:
HER2a
Cancer is a disease of extraordinary diversity
In terms of
•cell types of origin
•organ sites
•etiology
•
systemic predisposition
•
exposure
•
oncogenes
•pathological effects on the body
•rate of progression and survival
•response to particular therapies
The Hallmarks of Cancer
Hanahan & Weinberg (2011) Cell; Hanahan & Coussens (2012) Cancer Cell
Hallmarks as a cancer principle of organization
Hanahan & Weinberg (2000, 2011)
Definition of Hallmarks of Cancer
The hallmarks are acquired functional capabilities, that
allow tumors to:
Perform actions (functions)
• do so chronically
• coopting and corrupting otherwise carefully
orchestrated actions of cells and organs in the
body
First Hallmark of Cancer
The accelerator; full speed ahead; signals for
cells to to grow and divide with abandon
Second Hallmark of Cancer
The brakes have failed; signals to STOP are lost
Third Hallmark of Cancer
Avoiding assisted suicide of outlaw cells;
Loss of the inborn willingness of cells to die for
the benefit of the organism
The fourth hallmark
Circumventing a counting mechanism that prevents
continued cell division when a limit is reached
The fifth hallmark
Turning on new blood vessel growth, to feed and
nurture the growing mass of cancer cells
The sixth hallmark
Cancer cells grow by migrating and invading into
normal organs locally and throughout the body
And, in 2011, two emerging hallmarks
And, in 2011, two emerging hallmarks
Immune Surveillance of Tumours
Sir Macfarlane Burnet, 1964
“…in animals, …, inheritable genetic
changes must be common in somatic cells
and a proportion of these changes will
represent a step toward malignancy.
It is an evolutionary necessity that there
should be some mechanism for eliminating
or inactivating such potentially dangerous
mutant cells and it is postulated that this
mechanism is of immunological character.”
How are these hallmark capabilities acquired?
Via Enabling Characteristics
Enabling Characteristics are not functional capabilities
per se, i.e. they are not actions performed by cancer
cells and cancerous lesions
Rather, Enabling Characteristics are consequential
effects, things that have happened to cancer cells and
incipient lesions that facilitate acquisition of the hallmark
capabilities
Two enabling characteristics for acquiring hallmarks
The loss of mechanisms that maintain integrity of the
genome, resulting in appearance of (rare) mutations
Two enabling characteristics for acquiring hallmarks
Proliferative nests of cancer cells attract an inflammatory response by the
immune system
Inflammation that inadvertently includes immune cells that misdiagnose the
lesion as a wound to be healed, and thereby assist in hallmark capabilities
Tumors are complex association of cell types
similar to an individual “organ”
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer Cell
(CC)
Invasive
Cancer Cell
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer
Stem Cell
(CSC)
Cancer Cell
(CC)
Invasive
Cancer Cell
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer
Stem Cell
(CSC)
Cancer Cell
(CC)
Endothelial
Cell (EC)
Invasive
Cancer Cell
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer
Stem Cell
(CSC)
Cancer Cell
(CC)
Endothelial
Cell (EC)
Pericyte (PC)
Invasive
Cancer Cell
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer
Stem Cell
(CSC)
Cancer-Associated
Fibroblast (CAF)
Cancer Cell
(CC)
Endothelial
Cell (EC)
Pericyte (PC)
Invasive
Cancer Cell
Tumors are composed of an assemblage of
cell types that communicate and collaborate
Cancer
Stem Cell
(CSC)
Cancer-Associated
Fibroblast (CAF)
Cancer Cell
(CC)
Tumor-Promoting
Inflammatory
Cells (TPIC)
Endothelial
Cell (EC)
Pericyte (PC)
Invasive
Cancer Cell
Multiple normal cell types are recruited to be components
of tumors, helping to provide hallmark capabilities
Cancer
Stem Cell
(CSC)
Cancer-Associated
Fibroblast (CAF)
Cancer Cell
(CC)
Tumor-Promoting
Inflammatory
Cells (TPIC)
Endothelial
Cell (EC)
Pericyte (PC)
Invasive
Cancer Cell
Stromal cells functionally contribute to 7 of 8 hallmarks
Hanahan & Coussens (2012) Cancer Cell
Hallmarks : Applications to Cancer Medicine?
Remarkable responses in patients
with metastatic melanoma treated with
the B-Raf inhibitor vemurafenib
Finn et al
BMC Medicine
2012
Remarkable, but often transitory
responses in patients with metastatic melanoma
treated with the B-Raf inhibitor vemurafenib
Finn et al
BMC Medicine
2012
Remarkable responses in patients
with metastatic NSCLC treated with
the ALK inhibitor crizotinib
Median PFS is
~8 – 10 months
Emergence of
resistant
clonogens
Pre-crizotinib
2 months on
crizotinib
Targeting individual hallmark capabilities is not working so
well (EGFR, ALK, BRAF, anti-angiogenesis)
What about hitting individual
hallmarks at multiple nodes?
2012
Maybe by co-targeting multiple hallmarks, it will be difficult for
tumors to adapt, resulting in more enduring responses ?
B-Raf inhibitor
Additional complexity
Changes in Clonal Composition over Time
Aparicio S, Caldas C. N Engl J Med 2013;368:842-851
Cortesy of Charles Swanton
Phylogenetic trees of the patient's tumor over the course of therapy.
Crispin T. Hiley, and Charles Swanton Cancer Discov
2016;6:122-124
Fig. 1 Heterogeneity and prognostic value of neoantigen landscape in primary NSCLC.
Nicholas McGranahan et al. Science 2016;science.aaf1490
Published by AAAS
Thanks to Doug Hanahan
Thanks for your attention