1. Curing Cancer 2015 update Jesse S. Boehm, Ph.D. Associate Director, Broad Institute Cancer Program

2. 2003201320152023 Empiric (organ) Precise (gene) Personalized (patient) Two decades of cancer medicine

3. 2015: A unprecedented moment in the history of cancer Before BRAF drug 6 weeks later Example: BRAF-mutant melanoma

4. 2015: Explosion of excitement around using the immune system to fight cancer NYT: “Is the cure for cancer inside you?” Amazing, unprecedented long term successes, never before seen! 60% of patients with late stage melanoma now alive at 18 months, vs. <5% previously Scientists are working to better predict which patients will respond MSKCC

5. 2015: The culture of science is changing – we are all becoming part of a cancer-curing ecosystem

6. Most tumor samples have not been readily available for study Technology, social media, and cultural changes now provide a new opportunity to engage cancer patients and directly partner with them in this research We are launching new approaches to directly engage cancer patients in research Only 5% of U.S. cancer patients are enrolled in clinical trials 85% of U.S. cancer patients are treated in community settings

7. A model of collaborative science Broad as a horizontal connector across multiple institutions

8. Broad Cancer Program Is another cancer research effort really needed? Potent synergy between innovation and scale; harnessing creativity of academia with the professional, goal-oriented focus of industry Collaborative, team-oriented approach (200+ scientists) to tackle what industry deems scientifically or financially “impossible;” New organizational model focused on community impact and public good; pilot projects (that won’t be solved by industry) catalyze worldwide effort

9. 2015: A unprecedented moment in the history of cancer Before BRAF drug 6 weeks later Example: BRAF-mutant melanoma

10. How did this happen? Identification in 2002 that the BRAF protein is mutated in melanoma Develop a powerful drug that blocks the BRAF protein Launch a focused clinical trial by enrolling only patients with molecular biomarker that predicts response Understand relationship between having the mutation and responding to therapy Clinical trials are thus smaller, faster and cheaper See amazing clinical success (~2009) and FDA approval (2011)

11. What is Cancer? An uncontrolled growth of cells newscenter.cancer.gov

12. An Uncontrolled Growth of Cells Healthy cells turn into the enemy divide too quickly or abnormally become abnormal shapes and sizes grow in all directions Cells stop listening to the body, which is telling them to stop!...................................... structural support dividing cells non-dividing cells normal skin skin cancer

13. What is Cancer? An uncontrolled growth of cells A family of similar diseases newscenter.cancer.gov

14. A family of similar diseases Leukemias and Lymphomas: from cells in the blood and immune system Sarcomas: from cells in supportive tissue Carcinomas: from cells which protect the body from air and internal fluids newscenter.cancer.gov

15. What is Cancer? An uncontrolled growth of cells A family of similar diseases A genetic disease caused by mutations newscenter.cancer.gov

16. Cancer is a genetic disease Normal CellsCancer Cells.................... Cancer cells harbor genetic alterations Point mutations Chromosomal deletions or amplifications

17. Common causes of cancer Chemicals (e.g. tobacco, asbestos) Certain viruses and bacteria (e.g. HPV) Radiation from the sun What do all of these have in common?

18. Common causes of cancer Chemicals (e.g. tobacco, asbestos) Certain viruses and bacteria (e.g. HPV) Radiation from the sun What do all of these have in common? They all lead to MUTATIONS in the DNA of your cells

19. Remarkable advances in cancer prevention Prevent nearly all cervical cancers!

20. Common causes of cancer Chemicals (e.g. tobacco, asbestos) Certain viruses and bacteria (e.g. HPV) Radiation from the sun What do all of these have in common? They all lead to MUTATIONS in the DNA of your cells Can also be predisposed to getting cancer by inheriting mutations from parents

21. Most of the known genes associated with cancer have been found by: Studying familial cancer syndromes (pedigrees) 1969 Li-Fraumeni Syndrome = mutated p53 1980sRetinoblastoma= mutated RB 1990Neurofibromatosis= mutated NF1 1990sBreast Cancer= mutated BRCA1/2 1996Cowden Syndrome= mutated PTEN Finding key genes that cause cancer (1969-2000)

22. 2001: Sequence of the human genome Could now analyze cancer genomes from tumors and look for differences!

23. germline somatic Characterization (Individual) Interpretation (Population) Using genomics to build the world’s first map of all genes that cause cancer B)Which genome alterations are statistically significant in the population (occur more than expected by chance)? A) What is the full set of genome alterations within each tumor?

24. Discovering Cancer Genes where we are now Mapping cancer genes highlights potential drug targets First cancer genome decoded in 2009 2015: Broad has mapped over 15,000 cancer genomes across >25 tumor types, produced computational tools widely used across the globe We will soon have the complete map of common mutations in every major cancer type Major discoveries in nearly every cancer type; genome-guided medicine becoming reality for patients

25. 2015: Rise of “precision cancer medicine” patienttumor clinical sequencing and pathology mutations (10-150) cancer drugs that each target one of the mutations Many cancer patients are now having their cancer genome sequenced to help predict which drugs to take!

26. Converting genome information into cancer therapeutics: two challenges Drugs exist today that block only 10% of the mutated genes Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable” Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers

27. Converting genome information into cancer therapeutics: two challenges Drugs exist today that block only 10% of the mutated genes Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable” Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers SOLUTION 1: AGGREGATE CLINICAL DATA ON GENETICS LINKED TO DRUG RESPONSES (GLOBAL ALLIANCE FOR GENOMICS AND HEALTH)

28. Can also learn information right from patients! Use genome to demystify “exceptional responders” Resurrect “failed” drugs by finding genes that allowed rare patients to respond!

29. Converting genome information into cancer therapeutics: two challenges Drugs exist today that block only 10% of the mutated genes Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable” Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers SOLUTION 1: AGGREGATE CLINICAL DATA ON GENETICS LINKED TO DRUG RESPONSES (GLOBAL ALLIANCE FOR GENOMICS AND HEALTH) SOLUTION 2: BUILD A CANCER DEPENDENCY MAP IN THE LABORATORY

30. Can grow cancers in the lab Peds002TW: Wilms Tumor AAO2: Pancreatic adenocarcinomaBT584: Brain metastasis of colon cancer JL16: Anaplastic thyroid cancer

31. Map genetics of lab models: Cancer Cell Line Encyclopedia 1000 cancer cell lines Barretina et al, Nature 2012 www.broadinstitute.org/ccle

32. Turn each gene off one at a time and assess cancer cell survival via RNAi or CRISPR/Cas9 Discovery in early 2000s that “RNA interference” could be used to silence genes; however, not very specific Discovery in 2013 of the amazing new “CRISPR” gene editing technique; has revolutionized biomedicine Can use these technologies to systematically turn off each gene in the genome and study effects on cancer survival CRISPR in action Steven Dixon

33. RNAi/CRISPR/small molecule assessments of essentiality genetic/molecular features Have the feature Do not have the feature Degree of vulnerability Feature status Towards a Complete Cancer Dependencies Map high low Make all data available to empower the scientific community Use statistical analyses to extract relationships

34. Work to develop a cancer drug and deliver to right patients

36. Curing disease is no longer something that only scientists do: in 2015 we are all becoming scientists Patients may hold the keys to curing disease within their genome and can partner with scientific teams in new ways Crowd-sourcing challenges lower barriers to participation invite smart (young) people to solve big problems Can propel science through careers in policy, law, counseling, advocacy, communication/marketing, technology, etc (in addition to research/medicine) If you go to the doctor, take medicine, vote, use internet or social media to source health information, you are already part of the scientific ecosystem!