Center for Hematologic Malignancies

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Presentation transcript:

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 Multiple Myeloma Leukemias growth of lymphocytes in lymph node and bone marrow Hodgkin, non-Hodgkin lymphoma with >100 subtypes Multiple Myeloma excess plasma cells in blood and bone marrow Bone lesions, kidney disease Leukemias Proliferation of circulating blood, bone marrow cells Acute (ALL, AML) and chronic (CLL, CML, MPN)

Blood Cancers 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 >10% of all new cancer cases 1.2 million people are living with, or have been treated for, a blood cancer 58,000 deaths each year from blood cancers Some of the greatest successes in the history of the war on cancer 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 World leaders in clinical/laboratory efforts in: - Leukemia, lymphoma, myeloma, transplant - Immunotherapy, targeted therapies, epigenetics Clinical Trials: - Numerous investigator-initiated/registration trials HemeOnc Tissue Bank: - An expanding resource for research - More then 100,000 vials banked and counting… Funding: - Many grants from NIH/NCI, Stand up to Cancer, LLS

Success Stories in Blood Cancers at MSKCC First trials of CAR-T cells for leukemia patients Leader in development of novel approaches to stem cell transplantation Have led the development of leukemia drugs which are now part of clinical practice – research to improve the standard of care worldwide Developed the first drugs for cutaneous T-cell lymphoma, providing the first good therapeutic options for patients with these rare lymphomas Recruited and supported >10 lab-based investigators who are world leaders in blood cancer research

Build on Our Strength: Gaols for MSK Heme Malignancies Recruit laboratory-based investigators in lymphoid malignancies (lymphoma, CLL, myeloma) Increase ability to attract collaborative grants State of the art computational infrastructure Ensure access to patient samples for translational/basic research Support for pilot projects/translational efforts encourage high risk, high reward research

New MSK Center for Hematoligic Malignancies Director: Ross Levine Administrator: Eder Paraiso, Sharon Sobel Translational Project Manager: Minal Patel Irene Phillip Chris Famulare Associate Director: Elli Papaemmanuil, PhD (Bioinformatics, analysis, genomics, operations, strategy) Bioinformatics: Franck Rapaport, PhD Pipeline manager Database Support Analysts Grants Support: Shane Mayack, PhD

Heme Malignancies – Translational Team Tremendous wealth of samples in HOTB - allow people to find and use our rich sample collection

External Funding 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 Integrate across diseases and across different aspects of expertise (immunotherapy, targeted therapy) We will provide leadership/assistance with Assembling teams/proposals Integrate clinical investigators with less grant-writing experience into collaborative grant efforts Allows Society support to be a multiplier->your investment will allow us to obtain additional, long-term/renewable external funding Engelman

Bioinformatics Increasing use of state-of-the-art profiling technologies to study patients with blood cancer (and all cancers) We have assembled and continue to grow a team of bioinformatics experts who can provide expertise with data analysis, especially around big data By having these experts in the center, we develop computational researchers with expertise, interest, and focus on blood cancers Engelman

Future of Blood Cancer Research Most patients currently are treated with chemotherapy, transplant, radiation therapy 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 The labs at MSK have been at the vanguard of laboratory studies which have identified the molecular events which drive blood cancers How can we translate this to clinical benefit? Engelman

AML Still Associated with Poor Overall Survival Note from NCCN: changed -> into arrow symbol (). 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-> genome-wide 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 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 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 An innovative effort to accelerate discovery and clinical translation in blood cancers Allows us to serve as a leader for laboratory/clinical research, adult/pediatric blood cancer efforts, and links between basic science and clinical translation Serve as the catalyst to increase research and to shorten the path from discovery to clinical application 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

Blood Cancer Research at MSK! Acknowledgements Elodie Pronier Olga Guryanova Sophie McKenney Hiro Kunimoto Gila Spitzer Andrew Dunbar Bobby Bowman NCI, LLS, NIDDK