Transcript Cancer Care and Research at DF/HCC in 2015 - Dana

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
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What Will DFCI Look Like
in 2015?
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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
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Revolutionary Times in
Cancer Research
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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
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Normal Cells Know When to Stop Growing
Brain
Liver
Stem Cell
Balanced Cell Growth
and Differentiation
Healthy Organ
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Normal Cells Know When
& How Often to Divide
Dying Cells
Stem Cells
Intestinal cells divide just often enough to exactly replace
the dying cells.
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Cancer Occurs When Cells Bypass
the Normal Signals to Stop Dividing
Brain Cancer
Liver Cancer
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Genes and the Proteins They Make
Control Cell Division
DNA
"Blueprints"
RNA
"Work Orders"
Proteins
"Hands"
Cells
"Bricks"
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Genes that Control Cell Division Make
Proteins that are “Regulated”
DNA
"Blueprints"
RNA
"Work Orders"
Proteins
"Hands"
Protein
modification
Cells
"Bricks"
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Cancer Occurs When Mutations in
Cell Division Genes Damage their Ability to be Regulated
DNA
Mutation
RNA
"Work Orders"
Proteins
Cells
"Blueprints"
"Hands"
Signal
always
“on”
"Bricks"
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New “Targeted” Therapies Block
the “On” Signal of Mutated Proteins
DNA
Mutation
RNA
Proteins
Cells
Signal
always
“on”
Targeted
Therapies
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Personalized Medicine
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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
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Impediments to the Implementation of
Personalized Medicine
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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
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Structure of Science at DFCI
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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
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New Structures Needed to Realize
Personalized Medicine
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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
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Center for Cancer
Genome Discovery
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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
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Cancer Tissue Acquisition
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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
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New Models Required for Mutation
Analysis on all DFCI Patients
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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
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IS/Computational Biology
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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
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The Personalized Medicine Paradox
in Oncology
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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
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How to Resolve the
Drug Development Paradox
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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
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Early Drug Development at DFCI
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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
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Testing New Drug Efficacy
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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
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New Kinds of Clinical Trials
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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
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Measuring “Target Acquisition” in
Next Generation Clinical Trials
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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
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Measuring “Target Acquisition” Using
Molecular Imaging
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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
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Clinical Research Institute
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Successful clinical trials of future require efficient, high
capacity trial infrastructure, ability to biopsy tumors during
trial, close association with pathologists, and state-of-theart 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
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DF/HCC’s Central Role
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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
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DFCI in 2015 -- Impacting Patients
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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
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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
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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
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Stimulate Translation of Research into Patient Care
Bridge Connections to the Smith Building
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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
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