Cancer Care and Research at DF/HCC in 2015

1. Cancer Care and Research at DF/HCC in 2015 Clinical Trials Education Office Research Education Series August 22, 2008 Barrett Rollins, MD, PhD Chief Scientific Officer, DFCI

2. What Will DFCI Look Likein 2015? • Driving forces for expansion will be ongoing commitment to basic discovery in cancer and implementation of “Personalized Medicine” • Today’s discussion • Overview of science behind personalized medicine • DFCI efforts to realize promise of personalized medicine • What expanded DFCI will look like in 2015

3. Revolutionary Times inCancer Research • Understanding disease mechanism has a huge impact on developing effective treatments • Pneumonia & antibiotics; heart disease & statins • Now at a similar stage in our understanding of cancer

4. Normal Cells Know When to Stop Growing Brain Liver Stem Cell Balanced Cell Growth and Differentiation Healthy Organ

5. Normal Cells Know When& How Often to Divide Dying Cells Stem Cells Intestinal cells divide just often enough to exactly replace the dying cells.

6. Cancer Occurs When Cells Bypass the Normal Signals to Stop Dividing Brain Cancer Liver Cancer

7. Genes and the Proteins They Make Control Cell Division DNA "Blueprints" RNA "Work Orders" Proteins "Hands" Cells "Bricks"

8. Genes that Control Cell Division Make Proteins that are “Regulated” DNA "Blueprints" RNA "Work Orders" Proteins "Hands" Protein modification Cells "Bricks"

9. Cancer Occurs When Mutations inCell Division Genes Damage their Ability to be Regulated Mutation DNA "Blueprints" RNA "Work Orders" Proteins "Hands" Signal always “on” Cells "Bricks"

10. New “Targeted” Therapies Blockthe “On” Signal of Mutated Proteins Mutation DNA RNA Targeted Therapies Proteins Signal always “on” Cells

11. Personalized Medicine • Newly diagnosed patient is seen at DF/HCC hospital • Tumor sample is obtained or imaging performed • Specific cancer-associated mutations are determined • Specific drug active against those mutations is prescribed

12. Impediments to the Implementation ofPersonalized Medicine • Requires knowledge of all mutations that cause human cancers • Currently only know about a handful • Bcr/abl in CML; kit in GIST; EGFR in lung cancer; b-raf in melanoma; etc. • Need to know all of the relevant mutations • Number isn’t infinite (every patient won’t be unique) but very large • Drugs are not available for every known mutation much less the ones remaining to be discovered

13. Structure of Science at DFCI • Academic departments • Academic home for faculty • Business of promotions & recruitments • Department-based science • Unstructured & can be revolutionary (although inefficient) • Dept-based faculty are independent contractors hired to do what interests them • Source of many advances including Gleevec, RNAi, etc. • Absolutely committed to this model • Anticipate 5-7% increase by 2015

14. New Structures Needed to Realize Personalized Medicine • Organizational units needed to address specific tasks • Grew out of Strategic Planning process • For research component of plan, Dr. Benz asked faculty to identify areas most likely to have impact on patients in next 10 years • Genesis of Integrative Research Centers

15. Center for CancerGenome Discovery • Contributes to identifying all of the mutations associated with human cancer • Houses faculty from different depts, all with an interest in genome analysis • Conduit to Broad Institute • Participant in NIH’s Cancer Genome Anatomy Project

16. Cancer Tissue Acquisition • Another potential impediment to realization of personalized medicine • Tissue can be acquired from some patients who are on clinical trials • Only 15-20% of DFCI patients are enrolled on trials • Center for Population Sciences developed Cohort Studies • Designed to capture information on 100% of DFCI patients • Consent forms also allow genetic analysis • Genome Center now working with PopSci Center to capture cancer mutation analysis on all DFCI patients

17. New Models Required for Mutation Analysis on all DFCI Patients • Mutation analysis is expensive & is not currently a reimbursed test • Several years of clinical trials will be required before this can be shown to be clinically useful • Tests need to be paid for • Need greatly expanded capacity for genotyping human samples • Larger genotyping footprint at DFCI • Difficult to fund until test is reimbursable • More interaction with Broad

18. IS/Computational Biology • Mutation analysis will generate enormous amounts of data • Mutation data only meaningful if they can be linked seamlessly to clinical data • This will be one of the goals of IS Strategic Planning • CompBio Program part of research component of Strategic Plan • Will develop new tools for storage & analysis of these data

19. The Personalized Medicine Paradoxin Oncology • Traditionally relied on partnerships with pharma to develop drugs • Pharma justifies R&D expenses for a drug on basis of market size for that drug • Message of personalized medicine is that there are dozens of genetic varieties for every cancer type • Science has transformed a large market for a single (partly effective) drug into several small markets for several (more effective) drugs • Many companies are not interested in assuming the risk of drug development for small markets

20. How to Resolve theDrug Development Paradox • The lesson of Gleevec • Novartis reluctant to develop Gleevec because market was small • But, if the drug is effective it will produce a growing population of survivors who are long-term consumers • Gleevec is now a $2B drug • Academic institutions can initiate drug development for smaller indications • Pharma will partner at a later stage of development

21. Early Drug Development at DFCI • Chemical Biology Program grew out of Strategic Plan • In-house development of small organic compounds targeted against products of genes with cancer-related mutations • Requires organic chemists on faculty • DFCI has hired 3 & has plans for more • Alliance with Dept. of Chemistry & Chemical Biology at Harvard University • Requires physical infrastructure • Chemistry labs are more expensive to fit out than molecular biology labs • DFCI of 2015 should have more chemistry space • Needs to be considered in long-range planning

22. Testing New Drug Efficacy • Clinical trial activity in next 5- 10 yrs will be quantitatively & qualitatively different • Volume of trials will expand with the increased number of new drugs available for testing • More drugs for more diseases should result in higher proportion of DFCI patients on trial • Clinical trial infrastructure will have to expand & become much more efficient

23. New Kinds of Clinical Trials • Traditional trials for non-targeted drugs measure tumor shrinkage or survival • Lots of time, money, & patient volunteerism are spent before it’s clear that a drug has failed • Trials for targeted drugs can use different endpoints • We have molecular tools that measure whether a drug has engaged its target

24. Measuring “Target Acquisition” in Next Generation Clinical Trials • Biopsy tumor during 1st cycle of therapy • Variety of molecular techniques can be used to assess whether drug has altered its target as intended • Many of these have been developed by Center for Molecular Oncologic Pathology (joint DFCI/BWH Pathology Center) • Requires partnering with surgeons & interventional radiologists • Success depends on finding a way to work with & incentivize our non-medical colleagues

25. Measuring “Target Acquisition” Using Molecular Imaging • MRI, PET, CT, ultrasound alone or in combination can theoretically be used to determine if a drug has altered its target • Substantial technology development still required • Nancy Lurie Marks Center for Preclinical Imaging at Harbor Campus will develop these technologies • Effort will intersect with Chemical Biology • Imaging techniques will require synthesis of new molecules • Will also require exotic, short-lived radioactive isotopes; DFCI of 2015 may be home to a cyclotron of its own

26. Clinical Research Institute • Successful clinical trials of future require efficient, high capacity trial infrastructure, ability to biopsy tumors during trial, close association with pathologists, and state-of-the-art imaging • Plan to organize these resources & make them available through Clinical Research Institute • Will also train next generation of clinical researchers • Effort led by Phil Kantoff, Chief Clinical Research Officer & Steve Koppel, trustee

27. DF/HCC’s Central Role • Scientific discovery still to be done • Identification of new targets, novel therapies against those targets, novel measurements of anti-tumor efficacy, etc • Work of DF/HCC membership as individual PIs, in SPORES, in PPGs • New collaborations around large projects (eg, chemistry) to achieve leverage • Clinical trials will determine whether new approaches are effective • Clinical trial infrastructure is a DF/HCC infrastructure • Findings must be disseminated into community • Has to be done with attention to disparities in disease & in healthcare delivery • All part of DF/HCC’s core mission

28. DFCI in 2015 -- Impacting Patients • Emphasis on bringing real impact to patient outcomes • Integrated Research Centers • Translating genomic, chemical, pathological, and imaging findings into new therapies • Robust clinical trial infrastructure • Devoted to high volume, high throughput, modern trials • Genotyping every tumor in every DF patient • Sophisticated techniques for handling and analyzing data • A physical structure that supports rapid translation

29. Yawkey Center for Cancer Care & Smith Provisional Programming (for discussion purposes only) SM 10: Stiles, Schmucker, Ma, Eck, Shih, Segal SM 9: Roberts, Iglehart, Sicinski, Zhao + New Hire SM 8: Livingston, Vidal, Quackenbush + New Hire

30. A 40,000 sf Floorplate Devoted to a Single Group of Diseases Infusion Private /Staff side Public side Exam Staff Elevators Connection to research in Smith Provider work areas

31. Stimulate Translation of Research into Patient Care Bridge Connections to the Smith Building

32. Yawkey Center for Cancer Care & Smith Provisional Programming (for discussion purposes only) SM 10: Stiles, Schmucker, Ma, Eck, Shih, Segal SM 9: Roberts, Iglehart, Sicinski, Zhao + New Hire SM 8: Livingston, Vidal, Quackenbush + New Hire