Principles of Cancer Biology and Therapy. Prof Dr Solange Peters, MD, PhD Cancer Center Lausanne Switzerland

Transcription

1 Principles of Cancer Biology and Therapy Prof Dr Solange Peters, MD, PhD Cancer Center Lausanne Switzerland

2 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

3 Cancer and Age Breast Colon ALL Testicular CNS NCCC

4 Cancer is a disease of extraordinary diversity In terms of cell types of origin organ sites

5 Nomenclature Benign Polyp Malignant Epithelial Carcinoma Mesenchyme Sarcoma Hematopoietic Leukemia Lymphoma Myeloma

6 Cancer is a disease of extraordinary diversity In terms of cell types of origin organ sites etiology

7 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)

8 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, Science 2015

9 Mutations frequency varies according to cancer type 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 Lawrence MS, et al. Nature

10 Melanomas and lung tumors display many more mutations than average, with~200 nonsynonymous mutations per tumor. These larger numbers reflect the involvement of potent mutagens. Accordingly, lung cancers from smokers have 10 times as many somatic mutations as those from nonsmokers. Vogelstein, Science 2013

11 Karyotype differences between a normal and cancer cell

12 Every cancer genome is uniquely altered from its host normal genome Happy families are all alike; every unhappy family is unhappy in its own way. Leo Tolstoy, Anna Karenina Normal human genomes are all (mostly) alike; every cancer genome is abnormal in its own way. Each cancer genome has a unique set of genome alterations from its normal host These alterations, however, are not random but act in common pathways and mechanisms Matt Meyerson

13 WE have been studying oncogenes Oncogenes myc, ras, src, abl, bcl2 Tumor suppressor genes p53, Rb, APC, MEN1, NF1 MicroRNA Transcriptome control

14 The paradigm of drivers alterations: lung adenocarcinoma

15 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 D1- mediated cell proliferation Perera, PNAS 2009

16 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

17 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

18 The Hallmarks of Cancer Hanahan & Weinberg (2011) Cell; Hanahan & Coussens (2012) Cancer Cell

19 Hallmarks as a cancer principle of organization Hanahan & Weinberg (2000, 2011)

20 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

21 First Hallmark of Cancer The accelerator; full speed ahead; signals for cells to to grow and divide with abandon

22 Second Hallmark of Cancer The brakes have failed; signals to STOP are lost

23 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

24 The fourth hallmark Circumventing a counting mechanism that prevents continued cell division when a limit is reached

25 The fifth hallmark Turning on new blood vessel growth, to feed and nurture the growing mass of cancer cells

26 The sixth hallmark Cancer cells grow by migrating and invading into normal organs locally and throughout the body

27 And, in 2011, two emerging hallmarks

28 And, in 2011, two emerging hallmarks

29 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.

30 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

31 Two enabling characteristics for acquiring hallmarks The loss of mechanisms that maintain integrity of the genome, resulting in appearance of (rare) mutations

32 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

33 Tumors are complex association of cell types similar to an individual organ

34 Tumors are composed of an assemblage of cell types that communicate and collaborate

35 Tumors are composed of an assemblage of cell types that communicate and collaborate Cancer Cell (CC) Invasive Cancer Cell

36 Tumors are composed of an assemblage of cell types that communicate and collaborate Cancer Stem Cell (CSC) Cancer Cell (CC) Invasive Cancer Cell

37 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

38 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

39 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

40 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

41 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

42 Stromal cells functionally contribute to 7 of 8 hallmarks Hanahan & Coussens (2012) Cancer Cell

43 Hallmarks : Applications to Cancer Medicine?

44 Finn et al BMC Medicine 2012 Remarkable responses in patients with metastatic melanoma treated with the B-Raf inhibitor vemurafenib

45 Remarkable, but often transitory responses in patients with metastatic melanoma treated with the B-Raf inhibitor vemurafenib Finn et al BMC Medicine 2012

46 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)

47 What about hitting individual hallmarks at multiple nodes? 2012

48 Maybe by co-targeting multiple hallmarks, it will be difficult for tumors to adapt, resulting in more enduring responses? B-Raf inhibitor

49 Additional complexity Changes in Clonal Composition over Time Aparicio S, Caldas C. N Engl J Med 2013;368:

50 Cortesy of Charles Swanton

51 Phylogenetic trees of the patient's tumor over the course of therapy. Crispin T. Hiley, and Charles Swanton Cancer Discov 2016;6:

52 Fig. 1 Heterogeneity and prognostic value of neoantigen landscape in primary NSCLC. Nicholas McGranahan et al. Science 2016;science.aaf1490 Published by AAAS

53 Thanks to Doug Hanahan Thanks for your attention