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

Perspective on the human genome in 7 words

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

How will we learn how to interpret the cancer genome?

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

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

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

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

Gene expression signatures reflect allele activity

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

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

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)

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)

Toward a comprehensive cancer dependency map

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