Lecture 1: Course Introduction and Cancer ʻby the Numbersʼ. biochemistry 4450a

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1 Lecture 1: Course Introduction and Cancer ʻby the Numbersʼ biochemistry 4450a Introduction Rationale for this course Course ʻPhilosophyʼ Course Outline Evaluation Themes Critical Thinking Cancer ʻby the numbersʼ

2 DAVID RODENHISER, PhD (Course Coordinator) Associate Professor, Depts of Paediatrics, Biochemistry, Oncology; UWO Principal Investigator, London Regional Cancer Centre Scientist: Child Health Research Institute Room A4-134 Victoria Research Laboratories My lab focuses on the environmental role of epigenetics in the processes of gene expression, breast cancer and embryonic development. FRED DICK, PhD Assistant Professor, Depts of Biochemistry, Oncology; UWO Principal Investigator, London Regional Cancer Centre Scientist: Child Health Research Institute Room A4-136 Victoria Research Laboratories My lab's research is focused on the fundamental mechanisms that regulate the mammalian cell cycle and how they are disrupted in cancer. CAROLINE SCHILD-POULTER, PhD Assistant Professor, Dept of Biochemistry, UWO Cell Biology Research Group, Robarts Research Institute My research program is centered on the study of the mechanisms implicated in the NHEJ DNA repair pathway.

3 4450A: Rationale for this course: - Provide an introduction to the molecular genetic basis of human cancers. - Recent breakthroughs in molecular genetics have lead to landmark advances in our understanding of the molecular causation and treatment of the multiple types of human Cancers. - Cancer will be presented as a consequence of interactions between a cell's genetic blueprint and the external environment that alters that cell's selective advantage over its neighbours.

4 4450A: Course Philosophy or Approach An overview of Cancer - as a disease process that is the flipside of development - many of the same genes, but inappropriately expressed or regulated Cancer as a set of diseases that are: - gene(s) specific and tissue(s) specific - cell gains a selective advantage relative to its neighbours - genes and epigenetic changes mediated by the external environment Molecular mechanisms that we know are contributing to Cancer New approaches: revert altered cells to normal, or eliminating those cells.

5 4450A: Course Philosophy or Approach We will: investigate key cellular pathways that are frequently targeted and hijacked in tumour cells leading to neoplasia, discuss the mechanisms by which environmental factors affect tumour development discuss novel cancer models and molecular therapies. Concepts Pathways Targeting

6 Cancer Research: a continuum from Labbench to Bedside Basic Science Darwin McClintock Folkman Selective advantage transposons Angiogenesis Translation Clinical applications Varmus Grissom House oncogenes profiling clinical

7 Cancer Research: a continuum from Labbench to Bedside Basic Biology Early Diagnosis Darwin McClintock Folkman Selective advantage transposons Angiogenesis Prognosis Prediction Treatment Followup Varmus Grissom House oncogenes profiling clinical

8 MT Lecture # Lecture # Q R/MT Lecture # Lecture # Q: Quiz R: Review MT:Midterm -: no class Biochemistry 4450a Lecture Schedule (2009): Tentative schedule: August 24, 2009 lecture 1: Course Introduction and Cancer 'by the Numbers' INTRODUCTION (Dr Rodenhiser) lecture 2: The Hallmarks of Cancer lecture 3: The 'Cancer Genes': Viral Oncogenes and Rb CONCEPTS lecture 4: The 'Cancer Genes': ras and p53 (Dr Dick) lecture 5: Multistage Progression and the two hit (more or less) hypothesis lecture 6: Genomic Instability: enabling Cancer progression lecture 7: Immortality and Senescence lecture 8: Model organisms used in Cancer Biology Quiz 50 minutes: October 8 (in class) lecture 9: Genome Integrity I: Apoptosis PATHWAYS lecture 10: DNA Repair overview (Dr Schild-Poulter) lecture 11: Nucleotide Excision Repair lecture 12: Colon Cancer lecture 13: Defects in the BRCA genes and Breast Cancer Review in class prior to midterm (optional) Midterm 2 hours tentative date: October 29th evening lecture 14: Gene-Environment interactions lecture 15: Epigenetics and Cancer: translating basic science to treatment TARGETING lecture 16: Metastasis and Angiogenesis (Dr Rodenhiser) lecture 17: Cancer Pharmacogenetics and Proteomics lecture 18: Molecular Diagnostics and Counselling lecture 19: Molecular Profiling of tumours: array technology lecture 20: New Cancer Therapies I: Antisense technologies lecture 21: New Cancer Therapies II: The concept of Viral therapies lecture 22: Targeting Cancer by Viral therapies: Reo lecture 23: Summing up, review; feedback Final exam 3 hours date to be determined

9 The 4450a website: Source for: Updates and Information is your source for: Lecture notes: pdf format Required Readings : pdf format

10 Evaluation, Expectations and Marking Philosophy : Critical Thinking: Synthesis and Coordination of thoughts and ideas Assembling facts into systems having complex inter-relationships How do these threads tie together the concepts What was the most important point presented? What concept was the most difficult to understand?

11 Evaluation, Expectations and Marking Philosophy : Evaluation Quiz 10% Midterm 30% Final 60% Short answer and Essay Provide facts and relate to question asked Narrative tell a story Organize your answer before you start writing

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13 biochemistry 4450a Recurring themes in this course: Multistep progression Genomic Instability Selective Advantage Ask yourself: How do the molecular pathways fit into these categories? Regulatory circuits and nodes

14 Critical Analysis of Cancer Research What is the Context of the Research?.. What is the Hypothesis? What were the Research Questions / Objectives? What was the Experimental Design? What did they discover? How does this Research impact on the field? What was asked? What did they do? What did they find? What does it mean?

15 Cancer by the numbers General cancer facts Canada.( Cancer is the leading cause of premature death (30% of potential years lost) An estimated 171,000 new cases of cancer and 75,300 deaths from cancer will occur in Canada in ,200 Canadians diagnosed each week On the basis of current incidence rates, 40% of Canadian women and 45% of men will develop cancer during their lifetimes. ~1 in 4 Canadians will die of cancer in their lifetimes (24% women; 29% men)

16 Cancer is primarily a disease of older Canadians... - Increased number of new cases of cancer is primarily due to an increasingly older population. - 42% of new cancer cases and 60% of deaths due to cancer occur among people > 70 years old. - Cancer incidence is rising in young women ages (breast). - For all cancers combined, 5 year survival increased from 80% ( 92 to 95) to 85% ( 01 to 04) - Cancer rate is children in constant since 1985; death rates have declined - 80% of children with cancer are either enrolled in a clinical trial or have been treated by a protocol established by a clincial trial.

17 (Canadian Cancer Society, 2009)

18 Three cancer types account for ~55% of the new cases: Males: prostate, lung (28%), and colorectal cancers Females: breast, lung (26%), and colorectal cancers Lung Cancer: leading cause of premature death due to cancer ~1/3 of cancer deaths in men and 1/4 in women. (and it s preventable!!!) In women: Since 1979 lung cancer cases have tripled (!) levelling off. Among men, prostate cancer is the most commonly diagnosed cancer, but lung cancer is the leading cause of death. - Lung cancer rates leveled off in the mid-1980s and have since consistently declined, (reflecting a drop in tobacco consumption beginning in the mid-1960s).

19 males incidence mortality

20 females incidence mortality

21 Breast Cancer: - incidence among women over 50 rose steadily, but gradually, between 1980s and 1990s (likely due to use of mammography, tendency to delay having kids and declines in hormone replacement therapy). - female breast cancer mortality rates have declined steadily since mid- 80s; about 2% decdrease per year (~30% total decrease). - The breast cancer mortality rate is at its lowest since There is evidence for improved survival due to both organized mammography screening and adjuvant therapies following breast cancer surgery.. Early diagnosis!. (cancer progression model)

22 Complex relationships between: Cancer type, Exposures Demographics and Treatment

23 What is the molecular basis for these various cancers? What are the Rules that govern the transformation of normal cells into malignant cancer. The Hallmarks of Cancer (Hanahan and Weinberg (2000); Cell 100: 57-70) normal tumour Normal breast and tumour immunostained for DNMT3b. Butcher and Rodenhiser (submitted to Cancer Research) Six essential alterations that dictate malignant growth: 1. Self sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Evasion of apoptosis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Tissue invasion and metastasis Enabling characteristic: Genomic Instability

24 For example the BREAST CANCER perspective alterations in cell physiology that define malignant growth: Widschwendter and Jones, 2002