Lecture 1: Course Introduction and Cancer ‘by the Numbers’

IntroductionRationale for this courseCourse ‘Philosophy’Course OutlineEvaluationThemesCritical ThinkingCancer ‘by the numbers’

DAVID RODENHISER, PhD (Course Coordinator)Associate ProfessorDepts of Paediatrics, Biochemistry, Oncology; UWOPrincipal Investigator, London Regional Cancer CentreScientist: Child Health Research Institutedrodenhi@uwo.ca Room A4-134 Victoria Research Laboratories

My lab focuses on the role of epigenetics in the processesof gene expression as it relates to breast cancer,development and the environment.

FRED DICK, PhDAssistant ProfessorDepts of Biochemistry, Oncology; UWOPrincipal Investigator, London Regional Cancer CentreScientist: Child Health Research Institutefdick@uwo.ca Room A4-136 Victoria Research Laboratories

My lab's research is focused on the fundamentalmechanisms that regulate the mammalian cell cycle andhow they are disrupted in cancer

Rationale for this course:

- This course will provide an introduction to the moleculargenetic basis of human cancers.

-Recent breakthroughs in molecular genetics have lead tolandmark advances in our understanding of the molecularcausation and treatment of the multiple types of humanCancers.

- Cancer will be presented as a consequence of interactionsbetween a cell's genetic blueprint and the external environmentthat alters that cell's selective advantage over its neighbours.

Rationale for this course:

We will:… investigate key cellular pathways that are frequentlytargeted and hijacked in tumour cells leading to neoplasia,… discuss the mechanisms by which environmental factorsaffect tumour development and… discuss novel cancer models and molecular therapies.

- This course will be a particularly valuable course to undergraduatestudents who are considering graduate work, medical school, or otherhealth professional programs.

Course ‘Philosophy’ or ApproachAn overview of ‘Cancer’as a disease process that is the ‘flipside’ of development

Cancer as a set of diseases that are:- gene(s) specific- tissue(s) specific- due to the acquisition by a cell of a selective advantage relative to its neighbours

- cell's genetic blueprint external environment alters that cell's selective advantage over its neighbours.

Presentation of the molecular mechanisms- that we know are contributing to Cancer

New approaches:- returning altered cells to normalcy, or eliminating those cells.

What is the molecular basis for these diseases?

What are the …‘rules that govern the transformation of normal cellsinto malignant cancer….’

Normal breast and tumourimmunostained for DNMT3b.Butcher and Rodenhiser (submittedto Cancer Research)

normal

tumour

The Hallmarks of Cancer(Hanahan and Weinberg (2000); Cell 100: 57-70)

Six essential alterations that dictate malignant growth:

1. Self sufficiency in growth signals2. Insensitivity to ‘anti-growth’ signals3. Evasion of apoptosis4. Limitless replicative potential5. Sustained angiogenesis6. Tissue invasion and metastasisEnabling characteristic: Genomic Instability

- 1

2 3

4 5

6 7

8 Q

9 10

11 12

R MT

13

14

15 16

17 18

19 20

21 22

23 -

lectures

Q: QuizR: ReviewMT:MidtermF: Final

Biochemistry 450a Lecture Schedule:Tentative schedule: September 6, 2007

http://www.biochem.uwo.ca/undergrad/450b/450bLectureNotes.html

lecture 1: Course Introduction and Cancer 'by the Numbers'lecture 2: The Hallmarks of Cancerlecture 3: The 'Cancer Genes': Viral Oncogenes and Rblecture 4: The 'Cancer Genes': ras and p53lecture 5: Multistage Progression and the two hit (more or less) hypothesislecture 6: Genomic Instability: enabling Cancer progressionlecture 7: Immortality and Senescencelecture 8: Model organisms used in Cancer Biology............... In Class Quiz … 50 minutes … October 4lecture 9: Genome Integrity I: Apoptosislecture 10: Genome Integrity II: The DNA Repair pathwayslecture 11: Defects in caretakers: Colon Cancer and HNPCClecture 12: Defects in the BRCA genes and Breast CancerReview class prior to midterm............... Midterm … 2 hours … tentative date: October 25lecture 13: Epigenetics and Cancer: translating basic science to treatmentlecture 14: Metastasis and Angiogenesislecture 15: NE Repair: the cell’s response to environmental damagelecture 16: Gene-Environment interactionslecture 17: Cancer Pharmacogenetics and Proteomicslecture 18: Molecular Diagnostics and Counsellinglecture 19: Molecular Profiling of tumours: array technologylecture 20: New Cancer Therapies I: Antisense technologieslecture 21: New Cancer Therapies II: The concept of Viral therapieslecture 22: Targeting Cancer by Viral therapies: Reolecture 23: And another thing … ; Summing up, review; feedback.............. Final exam … 3 hours …

CONCEPTS

INTRODUCTION

PATHWAYS

TARGETING

(Dr Dick)

(Dr Rodenhiser)

(Dr Rodenhiser)

(Dr Rodenhiser)

The website:

http://publish.uwo.ca/~drodenhi/Biochem450A.html

Source for:

Lecture notes: pdf format

Required Readings: pdf format

What was the most important point presented?What concept was the most difficult to understand?

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

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

(no makeup on quiz … midterm then is 40%

Expectations and Marking ‘Philosophy’:

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?

Multistep progression

Genomic Instability

Selective Advantage

Regulatory circuits and ‘nodes’

Recurring themes in this course:

Ask yourself:

How do the molecular pathwaysfit into these categories?

Your Research Approach …

What is the Context of your Research? ….. What is your Hypothesis?

What did you ask?

What did you do?

What did you find?

What does it mean?

What were your Research Questions / Objectives?

What was your Experimental Design?

What did you discover?

How does your Research impact on the field?

General cancer facts – Canada ….(www.cancer.ca)

Cancer is the leading cause of premature death (30% of potential years lost)

An estimated 159,900 new cases of cancer and 72,000 deaths from cancer will occur in Canada in 2007.

2,900 Canadians diagnosed each week

On the basis of current incidence rates, 39% of Canadian women and 44% of menwill develop cancer during their lifetimes.

1 in 4 Canadians will die of cancer in their lifetimes

Cancer by the numbers

Since 1988 …

Cancer is primarily a disease of older Canadians ..- increased number of new cases of cancer is primarily due to an increasinglyolder population

- 44% of new cancer cases and 60% of deaths due to cancer occur amongpeople > 70 years old.

- Cancer incidence in rising in young adults aged 20-29 and females up to 39.

- Mortality is declining for males at all ages and for females under 70.

- Declines are most rapid in children and adolescents (ages 0-19).

(Canadian Cancer Society, 2007)

males

incidence mortality

females

mortalityincidence

Three cancer types account for 50% of the new cases:

Males: prostate, lung, and colorectal cancersFemales: breast, lung, and colorectal cancers

Lung Cancer: leading cause of premature death due to cancer1/3 of cancer deaths in men and 1/4 in women. (and it’s preventable!!!)

Since 1977: in women: -lung cancer cases have tripled (!)

Among men, lung cancer rates leveled off in the mid-1980s and havesince consistently declined, reflecting a drop in tobacco consumptionbeginning in the mid-1960s.

Among women, smoking rates began to decline slightly only in the mid-1980s, thus benefits in terms of declining lung cancer rates have yetto become apparent.

Breast Cancer:

- incidence rose steadily, but gradually, between 1978 and 1999 has stabilized(increase likely due to use of mammography in the mid-1980s / 90s)

- However, since mid-1980s the mortality rates have declined … (1.2% /yr).

- The most recent actual data for 2003 showed the breast cancer mortality rate tobe at its lowest since 1950.

There is evidence for improved survival due to both organized mammographyscreening and adjuvant therapies following breast cancer surgery.

Colorectal Cancer:

- in both males and females incidences were stable between 1994-2003.

- mortality rates continue to decline … (1.3% and 1.7%/yr in men and women).

-Improved treatments, particularly chemotherapy

- Screening for CRC can reduce incidence and mortality

Approximately one in three Canadianswill develop cancer in his or her lifetime andone in four Canadians will die of cancer.

What is the molecular basis for these diseases?

What are the …‘rules that govern the transformation ofnormal cells into malignant cancer….’Normal breast and tumour

immunostained for DNMT3b.Butcher and Rodenhiser (submittedto Cancer Research)

normal

tumour

The Hallmarks of Cancer(Hanahan and Weinberg (2000); Cell 100: 57-70)

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

Widschwendter and Jones, 2002

For example …Alterations in cell

physiology thatdefine malignant

growth:

the BREASTCANCER

perspective