1. Cancer – a disease of many mutations
No two tumors are identical (or homogeneous), but are there common mutations that could help guide drug design?

2. Bert Vogelstein discusses the biology of cancer
Clips 5-13
13 minutes

3. Let’s look at the stages in an epithelium
An epithelium is a layer of single cells surrounding a tissue
Normal epithelium
Cells adhere to each other and a matrix in an organized manner
Benign (in situ) tumors
Cells lose orderly geometry and associate improperly
Cells are still contained within the tissue boundary (blue)
Benign tumors can be VERY LARGE!
Majority of cancers originate in epithelia

4. Benign tumor is contained within the tissue boundary
Malignant tumors break through the tissue boundaries
Many secrete proteases that digest the matrix surrounding the tissue
Metastatic tumors move to new sites in the body (meta-statis = “new place”)

5. Pathologists can identify cancers by their appearance
Pap smears are used to detect cervical cancer
Normal
Malignant
Metastatic
Cervical cancer detected with a Pap smear 2

6. Hallmarks of cancer
The challenge: to identify genes responsible for each of these characteristics
Cell 100:57-70 (2000)

7. Many of the genes commonly mutated in cancer are often classified as:
Oncogenes:
drive growth
mutation generates super-active protein
Tumor suppressor genes:
arrest growth, signal suicide
mutations inactivate these
include many checkpoint genes
DNA repair genes:
repair DNA damage
mutations inactivate these

8. Bert Vogelstein discusses the genetics of cancer
Clips ( 10 minutes)
10 minutes

9. Random mutations accumulate throughout life
Repair processes are not 100% efficient
Intrinsic mutation includes errors in DNA replication and repair
Environmental factors may increase the mutation rate

10. Vast majority of tumors appear in adult life
Frequency increases with age
Intrinsic processes
Environment and lifestyle
Mutations in growth promoting/suppressing genes are present in cancer cells
Research challenge: distinguish passenger (circles) and driver (stars) mutations
As tumors develop, the cell may become unstable, causing mutations to accumulate at a higher rate - mutator phenotype

11. In later (more lethal) stages of cancer, transformed cells break through the normal tissue barriers and move to new locations
Intrinsic processes
Environment and lifestyle
Mutator phenotype

12. The timelines for acquiring mutations vary in each tumor
Oncogene mutations usually occur early in the sequence
Most tumors have an oncogene mutation
Genes implicated in metastasis typically acquire mutations late in cancer progression

13. Why sequence cancer genomes?
The hope: Chemists may be able to design highly targeted drugs that inhibit proteins implicated in tumorigenesis with minimal damage to normal cells

14. Challenge of drug design – identifying target proteins that drive cancer
This growth-promoting pathways involves several proteins that are frequently over-produced or mutated in cancers.

15. Much data has been collected!

16. Mutations in the EGFR gene show tumor-specific patterns
MS Lawrence et al. Nature 505, (2014) doi: /nature12912

17. Some genes are frequently mutated in a particular kind of cancer
Very few genes are mutated with >20% frequency
Most genes are mutated at intermediate frequencies (2-20%)