THE BIOLOGY OF CANCER. Dr Jim Edwards Medical Oncologist Canterbury District Health Board

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1 THE BIOLOGY OF CANCER Dr Jim Edwards Medical Oncologist Canterbury District Health Board

2 OVERVIEW Historical perspectives on Cancer Biology? Important principles of Cancer Biology Why is understanding cancer biology important? Examples of how understanding cancer biology has lead to significant progress.

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4 WHAT IS CANCER? A disease caused by an uncontrolled division of abnormal cells in a part of the body. Some cancers may eventually spread into other tissues Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive.

5 Genetic Disease Somatic Germline HOW CANCER ARISES Cancer cells generally contain more genetic changes than normal cells

6 DRIVERS OF CANCER Proto-oncogenes When abnormal, or inappropriately active are termed ONCOGENES Tumour suppressor genes DNA repair genes Involved in fixing damaged DNA

7 You keep talking about Bowel cancer Doc, but I thought I had liver cancer now Metastatic sites GENERALLY have the same microscopic appearances as the primary Metastatic cells usually retain some, not all, of the molecular changes present in the primary WHEN CANCER SPREADS

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9 70 80 million years ago Evidence of cancer cells in dinosaur fossils, found in million years ago The oldest known hominid malignant tumour was found in Homo erectus, or Australopithecus, by Louis Leakey in Possibly Burkitt lymphoma

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11 Origin of the Word Cancer Carcinos, Carcinoma. Refers to the Crab Celsus (Roman Physician BC) Translated the Greek term into CANCER, latin for crab Galen (Greek physician AD) First used the term oncos (Greek for swelling) Hippocrates believed cancer was caused by an imbalance of four bodily humors: yellow bile, black bile, blood, and phlegm Hippocrates ( BC). British Museum 2 nd or 3 rd Century BC

12 Chinese description and images of Breast Cancer Circa 250 BC Describes 5 forms of therapy Spiritual, Pharmacological, Diet, Acupuncture, plus treatment of respiratory disease

13 100AD Galen removed some tumours surgically Believed melancholia was the main cause of breast cancer Treated with diet, exorcism, and topical applications AD Caustic Pastes (arsenic) Blood letting Symbolic charms Herbal medicine

14 Andreas Vesalius Johannes Scultetus

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16 THE HALLMARKS OF CANCER Hanahan and Weinberg. Cell, Vol 100, Issue 1, 7 January 2000 Hanahan and Weinberg Cell, Vol 144, Issue 5, 4 March 2011

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18 Produce growth factor ligand Stimulate normal cells in tumour associated stroma Which in turn produce growth factors Elevating the level of receptor proteins Constitutive activation of signalling pathway Leads to growth factor independence

19 Powerful mechanisms exist to negatively regulate cell proliferation Often rely on the actions of TUMOUR SUPPRESSOR GENES. Retinoblastoma (RB) TP53 Two key complementary cellular regulatory circuits. RB protein Integrates signals from intracellular and extracellular sources Decides if cell should proceed through its growth and division cycle TP53 Receives inputs from stress and abnormality sesnors within intracellular systems. Genomic damage, suboptimal levels of glucose, oxygen, growth promoting signals Call a halt to further cell cycle progression under conditions are improved. Triggers APOPTOSIS if overwhelming damage has occurred. Contact Inhibition

20 Programmed Cell Death or Apoptosis Composed of Upstream regulators Extracellular (Extrinsic) Intracellular (Intrinsic) Downstream effectors Apoptotic trigger Counterbalancing pro- and antiapoptotic members of Bcl-2 family DNA damage sensor Insufficient survival factor signalling (eg IL 3, or Insulin like growth factor 1/2) Hyperactive signalling by certain oncoproteins eg MYC

21 Normal cell lineages have a limited number of successive cell growth and division cycles. Senescence Crisis Telomeres shorten progressively with each division Leads to crisis. Telomerase often abundant in cancer cells May be lacking in incipient neoplasms

22 Tumours require nutrients and oxygen, as well as the ability to evacuate waste, and carbon dioxide Tumour associated neovasculature (via angiogenesis) achieves this. Angiogenic Switch Causes normally quiescent vasculature to sprout new vessels to sustain growing tumour. Governed by balance between pro angiogenic (eg VEGF-A, FGF) and antiangiogenic (eg Thrombospondin -1) factors VEGF gene expression upregulated by hypoxia and oncogene signalling Vasculature is typically aberrant Probably contributes to microscopic premalignant phase.

23 Concept of invasion-metastasis cascade. Local invasion Intravasation Transit via lymphatics and blood Extravasation into parenchyma Development of micrometastases Growth in macroscopic tumours. Epithelial-mesenchymal transition (EMT) Co-opted process involved in the various steps of embrygenesis and wound healing.

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26 SOME EXAMPLES

27 CERVICAL CANCER In 1713 it was observed that nuns had a virtual absence of cervical cancer Raising the idea that celibacy may be protective. Pap test developed in 1928 Screening introduced in 1950 s Incidence of Invasive Cervical cancer dropped by 70% by mid 1980 s Harms include overdiagnosis, cost, discomfort, anxiety, Reproductive effects of treatment.

28 1949 Human Papilloma Virus first seen on electron microscope 1976 HPV DNA identified in cervical cancer

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30 Better to prevent than screen CERVICAL CANCER

31 LUNG CANCER 1912 Adler publishes book which reviews lung cancer There were only 374 verified cases world wide Smoking becomes popularized during WW1 Between 1922 and 1947 deaths rise from 612 to 9287 in England Doll and Hill publish landmark article associating smoking with lung cancer BMJ 1950;2:739 By 2005 deaths from lung cancer exceed those from Breast, Colon, and prostate cancer. The most preventable cancer?

32 Metastatic disease has a poor outlook Median survival 6-9 months Historically treated with chemotherapy Response rates low Small improvements in survival Prior to mid 2000 s all patients treated the same LUNG CANCER

33 Epidermal Growth Factor receptor. Highly expressed in NSCLC High levels thought to be associated with poor prognosis Tyrosine Kinase inhibitors Monoclonal antibodies. Gefitinib Early studies showed response in lung cancer Response rate 10 20%

34 1100 patient with NSCLC 46% adenocarcinoma 30% Squamous cell Chemo +/- Gefitinib made no difference to OS of PFS

35 Most patients treated with gefitinib have no response. Some have dramatic responses 9 patients tested for mutations in the EGFR gene. 8 patients had mutations.

36 Mutation status, but not gene copy number influenced benefit from EGFR blockade

37 Progression free survival improved from 5.5 months to 11months Response rate increase from 34% to 63% Less (different) toxicity

38 Chan et al. Translational Lung Cancer Research Feb 2016

39 HIF respond to hypoxia to promote angiogenesis. HIF under VHL regulation VHL frequently inactivated by mutation in RCC Stimulation of angiogenesis Logical target for treatment. RENAL CANCER

40 September 2011 August 2013

41 Multiple other agents targeting VEGF Axitinib Pazopanib Bevacizumab ( +IFN)

42 BREAST CANCER THE STORY OF TRASTUZUMAB Discovered initially in 1982 from a rat with neuroblastoma Termed neu by Weinberg Human homolog discovered in 1984 Noted to resemble Human EGF Receptor Termed Her-2 Discovered to be amplified is some breast cancer samples in 1986 (Denis Slamon) Noted to be associated with a worse prognosis First antibody directed against Her-2 produced at Genentech in First humanized antibody in First patients treated 1992.

43 Slamon et al. NEJM March Response rate increased Progression free survival increased 4.6 v 7.4 months Overall survival increased 20.3 v 25.1 months Also identified cardiac toxicity of Trastuzumab

44 THE TRASTUZUMAB STORY Exemplifies how the knowledge of biology of a cancer is so important Prior to the 1990 s there was no such thing as Her 2 positive breast cancer The discovery of a Driver oncogene. The idea that we might know what drives the cancer The elucidation that its presence is associated with worse outcomes This knowledge reduces (a little) the extreme heterogenous behaviour of metastatic breast cancer. The creation of a drug that targets only the gene product (Her 2 receptor) and improves survival with minimal (compared to other drugs of the day) toxicity

45 THE BIOLOGY OF (BREAST) CANCER STORY Continues Intrinsic subtypes BRCAness New Drugs Pertuzumab Incremental gains Increasing survival Reducing toxicity

46 Perhaps surgery, radiation therapy, and chemotherapy will one day be considered as archaic as blood letting and leeches.

47 Prognosis Eg TNB, double hit, BRAF, Predictive HER -2, EGFR, PARP Diagnosis GIST, BurKitt Genetics?? Prevention HPV vaccination Treatment development Renal Ca/VEGF

48 LUNG CANCER

49 OTHER TYPES OF TISSUE CHANGES