1. Preclinical Accelerators of Precision Medicine Todd R. Golub, M.D.
Broad Institute

2. Perspective on the human genome in 7 words

3. Genome: Bought the book, hard to read. -- Eric Lander, 2003
Perspective on the human genome in 7 words
Genome: Bought the book, hard to read.
-- Eric Lander, 2003

4. How will we learn how to interpret the cancer genome?

5. How will we learn how to interpret the cancer genome?
By making genotype-clinical response associations

6. How will we learn how to interpret the cancer genome?
By making genotype-clinical response associations
By using systematic experimental models (even if imperfect) to guide clinical investigation

7. Interpreting variant alleles
It’s now possible to synthesize all possible alleles of any cancer gene (e.g. EGFR)

8. gene expression profiling
Interpreting variant alleles
It’s now possible to synthesize all possible alleles of any cancer gene (e.g. EGFR)
96h
gene expression profiling
library of ORF alleles
A549 lung cells

9. Gene expression signatures reflect allele activity

10. Gene expression signatures reflect allele activity
Systematic assessment of all alleles for transforming and drug sensitivity also now feasible

11. WNT pathway Even known mutations often have no drugs targeting them
J. Rosenbluh, M. Giannakis

12. WNT pathway Even known mutations often have no drugs targeting them
Need to catalyze early drug discovery efforts against “undruggable” targets (e.g. NCI RAS initiative)

13. WNT pathway Even known mutations often have no drugs targeting them
Need to catalyze early drug discovery efforts against “undruggable” targets (e.g. NCI RAS initiative)
Need to systematically discover vulnerabilities associated with particular genotypes (Cancer Dependency Map)

14. Toward a comprehensive cancer dependency map

15. Recommendations
Generate high quality functional look up tables for all alleles of known cancer genes
Generate a comprehensive Cancer Dependency Map that relates molecular features of tumor cells to their vulnerabilities
Use this experimental information to inform priority of clinical trials and interpretation of clinical data