Download Center for Hematologic Malignancies

Center for Hematologic Malignancies
Ross L. Levine, M.D.
Human Oncology and Pathogenesis Program
Leukemia Service, Department of Medicine
Center for Epigenetics Research
Center for Hematologic Malignancies
Memorial Sloan Kettering Cancer Center
Blood Cancers
Lymphomas
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Multiple Myeloma
growth of lymphocytes in lymph node and bone marrow
Hodgkin, non-Hodgkin lymphoma with >100 subtypes
Leukemias
- Proliferation of circulating blood,
bone marrow cells
- Acute (ALL, AML) and chronic (CLL,
CML, MPN)
excess plasma cells in blood
and bone marrow
Bone lesions, kidney disease
Blood Cancers
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171,500 people in the US will be diagnosed with a blood cancer this
year: 81,000 lymphoma, 60,000 leukemia, and 30,000 myeloma new
cases each year
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>10% of all new cancer cases
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1.2 million people are living with, or have been treated for, a blood
cancer
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58,000 deaths each year from blood cancers
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Some of the greatest successes in the history of the war on cancer
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First cure of any cancer (pediatric ALL)
Development of stem cell transplant
First molecularly targeted therapy (Imatinib/Gleevec for CML)
Many seminal discoveries in the blood cancer field
Heme Malignancies at MSKCC
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World leaders in clinical/laboratory efforts in:
- Leukemia, lymphoma, myeloma, transplant
- Immunotherapy, targeted therapies, epigenetics
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Clinical Trials:
- Numerous investigator-initiated/registration trials
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HemeOnc Tissue Bank:
- An expanding resource for research
- More then 100,000 vials banked and counting…
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Funding:
- Many grants from NIH/NCI, Stand up to Cancer, LLS
Success Stories in Blood Cancers at MSKCC
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First trials of CAR-T cells for leukemia patients
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Leader in development of novel approaches to stem cell
transplantation
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Have led the development of leukemia drugs which are now part of
clinical practice – research to improve the standard of care
worldwide
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Developed the first drugs for cutaneous T-cell lymphoma, providing
the first good therapeutic options for patients with these rare
lymphomas
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Recruited and supported >10 lab-based investigators who are
world leaders in blood cancer research
Build on Our Strength: Gaols for MSK Heme
Malignancies
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Recruit laboratory-based investigators in lymphoid
malignancies (lymphoma, CLL, myeloma)
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Increase ability to attract collaborative grants
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State of the art computational infrastructure
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Ensure access to patient samples for translational/basic
research
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Support for pilot projects/translational efforts encourage high
risk, high reward research
New MSK Center for Hematoligic Malignancies
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Director: Ross Levine
• Administrator: Eder Paraiso, Sharon Sobel
• Translational Project Manager: Minal Patel
• Irene Phillip
• Chris Famulare
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Associate Director: Elli Papaemmanuil, PhD
(Bioinformatics, analysis, genomics, operations,
strategy)
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Bioinformatics: Franck Rapaport, PhD
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Pipeline manager
Database Support
Analysts
Grants Support: Shane Mayack, PhD
Heme Malignancies – Translational Team
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Tremendous wealth of samples in HOTB - allow people to find
and use our rich sample collection
External Funding
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Given our national/international leadership we are competitive for
grants from NIH, LLS, other foundations
• Key to fund our research and to further extend our international
leadership position in blood cancers
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Integrate across diseases and across different aspects of expertise
(immunotherapy, targeted therapy)
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We will provide leadership/assistance with
• Assembling teams/proposals
• Integrate clinical investigators with less grant-writing experience
into collaborative grant efforts
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Allows Society support to be a multiplier->your investment will allow
us to obtain additional, long-term/renewable external funding
Bioinformatics
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Increasing use of state-of-the-art profiling technologies to
study patients with blood cancer (and all cancers)
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We have assembled and continue to grow a team of
bioinformatics experts who can provide expertise with data
analysis, especially around big data
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By having these experts in the center, we develop
computational researchers with expertise, interest, and focus
on blood cancers
Future of Blood Cancer Research
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Most patients currently are treated with chemotherapy,
transplant, radiation therapy
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Effective, but highly toxic, risk of short and long term side effects
When patients fail these therapies, there are few options which offer
the chance for cure
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The labs at MSK have been at the vanguard of laboratory
studies which have identified the molecular events which drive
blood cancers
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How can we translate this to clinical benefit?
AML Still Associated with Poor Overall
Survival
• Even with intensive induction chemotherapy/transplantation most patients
die of their disease new insights are needed
• Only 2 classes of agents approved for AML in 3 decates (hypomethylating
agents, gemtuzumab)
Issa, Kantarjian et al, Cancer 2008
IDH2 mutations in AML
• Genome sequencing and metabolism
studies (Thompson, Levine labs) led
to identification of IDH2 mutations in
acute myeloid leukemia
• The overall incidence of IDH1/2
mutations is 15-30%, most common
in older patients
• How do these mutations contribute to
leukemia development?
• Is IDH2 a therapeutic target?
Ward et al. Cancer Cell 2010
Marcucci et al JCO 2010
Gross et al. J Ex Med 2010
AML in IDH2 mutant mice
Resistant to chemotherapy, similar to AML patients with
same mutations
What are the key pathways which drive AML-> genomewide DNA methylation profiling
Epigenetic Silencing in IDH-mutant AML
TET2-mutant AML Normal stem cells
GATA2, master regulator of hematopoiesis, is silenced
in IDH-mutant AML
What happens when you restore Gata2 in AML cells?
Rexpression of GATA2 abrogates in vivo
transformation of FLT3/TET2-mutant AML cells
MIGR1
Gata1
Gata2
5FU
Tet2-/- Flt3-ITD
BM cells
sort
transplant
Recipients
Adding back a
single silenced
gene can make
the leukemias go
away over time
In Vivo efficacy of IDH2 Inhibition with AG221
- In vitro and in vivo assays show significant efficacy
- See evidence of differentiation in vivo with reduced blasts, expansion of mature
myeloid cells
- Clinical trials of AG-221, IDH2-specific inhibitor in relapsed/refractory IDH2-mutant
AML (Eytan Stein, PI)
AG-221 in Relapsed/Refractory IDH2-mutant AML
C1
C2
C3
C4
CR
30 MG
BID
C5
C6
C7
Transplant
CRp
Bone Fracture,
Death Unrelated
CR
PR
CR*
CR
50 MG
BID
PR
On Study
Off Study
Response
Bone Marrow
CRi
CR**
75 MG
BID
100 MG
QD
PR
CR
CRp
100 MG
BID
150 MG
QD
PR
PR
• Significant clinical activity in AML patients with IDH2 mutations (required for
enrollment
• Evidence of differentiation in vivo with neutrophil expansion followed by clinical
response
Stein et al. ASH 2015
AG-221 in Relapsed/Refractory IDH2-mutant AML
CR: 6/7 patients have neutrophils with IDH2 mutations (and all other mutations)
present at diagnosis (3-18 months)
Center for Hematologic Malignancies
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An innovative effort to accelerate discovery and clinical
translation in blood cancers
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Allows us to serve as a leader for laboratory/clinical research,
adult/pediatric blood cancer efforts, and links between basic
science and clinical translation
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Serve as the catalyst to increase research and to shorten the
path from discovery to clinical application
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Will allow us to continue to lead the world in blood cancer
research and clinical care and to attract the best talent to blood
cancer efforts at MSK
BloodAcknowledgements
Cancer Research at MSK!
• Elodie Pronier
• Olga Guryanova
• Sophie McKenney
• Hiro Kunimoto
• Gila Spitzer
• Andrew Dunbar
• Bobby Bowman
• NCI, LLS, NIDDK