57th ASH Annual Meeting and Exposition (December 5-8, 2015): 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Acute Myeloid Leukemia: An Understanding of Molecular Mechanisms Guides Rational Drug Combinations

Molecular Pharmacology and Drug Resistance in Myeloid Diseases Oral and Poster Abstracts
Oral

W307, Level 3 (Orange County Convention Center)

Moderators:

Hetty E. Carraway, MD, MBA, Cleveland Clinic and Benjamin S Braun, MD, PhD, University of California, San Francisco

Disclosures:

No relevant conflicts of interest to declare.

2:45 PM

BCL-2 Inhibition By ABT-199 (Venetoclax/GDC-0199) and p53 Activation By RG7388 (Idasanutlin) Reciprocally Overcome Leukemia Apoptosis Resistance to Either Strategy Alone: Efficacy and Mechanisms

Rongqing Pan, MS^1,2, Vivian Ruvolo, MS¹^*, Hong Mu, MD, PhD³^*, Zhuanzhen Zheng, PhD¹, Joel Leverson, PhD⁴^*, Kensuke Kojima, PhD¹, Marina Konopleva, MD, PhD¹, Gwen Nichols, MD⁵ and Michael Andreeff, MD, PhD³

¹Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
²The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX
³Section of Molecular Hematology and Therapy, Leukemia Department, UT MD Anderson Cancer Center, Houston, TX
⁴AbbVie Inc., North Chicago, IL
⁵Roche Pharma Research & Early Development, Roche Innovation Center, New York, NY

3:00 PM

674

Dual Inhibition of MDM2 and BET Cooperate to Eradicate Acute Myeloid Leukemia

Anne-Louise Latif, MBChB¹^*, John J Cole¹^*, Joana Monteiro Campos²^*, William Clark¹^*, Lynn McGarry, PhD¹^*, Claire Brock¹^*, Ashley Newcombe¹^*, Karen Keeshan, PhD², Mhairi Copland, BSc (Hons) MB ChB PhD FRCP FRCPath² and Peter D Adams, PhD¹^*

¹Beatson Institute for Cancer Research, University of Glasgow, Glasgow, United Kingdom
²Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, United Kingdom

3:15 PM

675

BRD4 Proteolysis Targeting Chimera (PROTAC) Leads to Sustained Degradation of BRD4 with Broad Activity Against Acute Leukemias and Overcomes Stroma Mediated Resistance By Modulating Surface Expression of CXCR4

Sujan Piya¹^*, Teresa McQueen²^*, Duncan Mak, BSc, MPhil²^*, Marina Konopleva, MD, PhD³, Patrick Zweidler-McKay, MD, PhD⁴, Jing Lu, Ph.D.⁵^*, Yimin Qian, Ph.D.⁵^*, Michael Andreeff, MD, PhD⁶ and Gautam Borthakur, MD⁷

¹Leukemia, UT MD Anderson Cancer Center, Houston, TX
²Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
³Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
⁴Department of Pediatrics Research, The University of Texas M D Anderson Cancer Center, Houston, TX
⁵Arvinas, LLC, New Haven, CT
⁶Section of Molecular Hematology and Therapy, Leukemia Department, UT MD Anderson Cancer Center, Houston, TX
⁷Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

3:30 PM

676

Azacitidine in Combination with the Selective FLT3 Kinase Inhibitor Crenolanib Effectively Disrupts Stromal Protection of CD34+ Leukemia-Initiating Cells (LIC) in FLT3-ITD+ Acute Myeloid Leukemia (AML)

Anne-Kathrin Garz, M.Sc.^1,2^*, Stefan Habringer^2,3^*, Saskia Wolf¹^*, Binje Vick, PhD^2,4^*, Marie-Theresa Weickert, M.Sc.¹^*, Irmela Jeremias, MD^2,5,6^*, Karsten Spiekermann, MD^2,7, Christian Peschel, MD^2,8, Robert A.J. Oostendorp, PhD¹^*, Ulrich Keller^2,3^* and Katharina S. Götze, MD^1,2

¹III. Department of Medicine, Hematology and Medical Oncology, Technical University of Munich, Munich, Germany
²German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Munich, Germany
³III. Department of Internal Medicine, Hematology and Medical Oncology, Technische Universität München, Munich, Germany
⁴Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany
⁵Research Unit Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany
⁶Department of Oncology, Dr. von Haunersches Kinderspital, Ludwig Maximilians University, Munich, Germany
⁷Department of Internal Medicine III, Ludwig-Maximilians-University, Munich, Germany
⁸III. Medizinische Klinik, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

3:45 PM

677

Recurrent Mutations in CCND3 Confer Clinical Resistance to FLT3 Inhibitors

Catherine C. Smith, MD¹, Aaron D. Viny, MD, MS², Evan S. Massi, BS¹^*, Cyriac Kandoth, PhD²^*, Nicholas D. Socci, PhD³^*, Henry Hsu, MD⁴^*, Brian West, PhD⁴^*, Gideon Bollag, PhD⁴, Barry S. Taylor, PhD⁵^*, Ross L. Levine, MD⁵ and Neil P. Shah¹

¹Department of Medicine, University of California at San Francisco, San Francisco, CA
²Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
³Department of Bioinformatics, Memorial Sloan Kettering Cancer Center, New York, NY
⁴Plexxikon Inc., Berkeley, CA
⁵Memorial Sloan Kettering Cancer Center, New York, NY

4:00 PM

678

Mechanisms of Resistance to 5-Azacytidine/Decitabine in MDS-AML and Pre-Clinical In Vivo Proof of Principle of Rational Solutions to Extend Response

Quteba Ebrahem¹^*, Reda Z. Mahfouz, MD/PhD², Lisa Durkin³^*, Mikkael A. Sekeres, MD, MS⁴, Anjali S. Advani, MD⁵, Hetty E. Carraway, MD, MBA⁵, Sudipto Mukherjee, MD, PhD⁵, Betty K. Hamilton, MD⁶, Aaron T. Gerds, MD, MS⁵, Ronald Sobecks, MD⁷, Frederic J. Reu, MD⁸, Eric D. Hsi, MD⁹, Jaroslaw P. Maciejewski, MD, Ph.D.¹⁰ and Yogenthiran Saunthararajah, M.D.¹¹

¹Cleveland Clinic, Cleveland, OH
²Department of Translational Hematology and Oncology Research, Taussing Cancer Institute, Cleveland Clinic, Cleveland, OH
³Laboratory Medicine, Robert J. Tomsich Pathology & Laboratory Medicine Institute. Cleveland Clinic, Cleveland, OH
⁴Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
⁵Leukemia Program, Cleveland Clinic, Cleveland, OH
⁶Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
⁷Blood and Marrow Transplant, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
⁸Taussig Cancer Institute, Department of Hematology & Medical Oncology, Cleveland Clinic, Cleveland, OH
⁹Laboratory Medicine, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
¹⁰Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
¹¹Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

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604.O1.6 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Acute Myeloid Leukemia: An Understanding of Molecular Mechanisms Guides Rational Drug Combinations