The Memorial Sloan Kettering Cancer Center SPORE in Leukemia

OVERALL ABSTRACT
Despite recent advances in the treatment of acute myeloid leukemia (AML), the majority of AML patients relapse
following treatment and the overall five-year survival rate for adults with AML remains 25-29%. Thus, an urgent
need to improve therapy for AML patients remains. The MSK SPORE in Leukemia will leverage collective efforts
to develop effective targeted therapies and immunotherapeutic approaches for several recurrent molecular
subtypes of AML, including some which lack therapeutic options entirely. The overall translational aims of the
MSK SPORE in Leukemia are to 1) interrogate genetic and molecular pathways required for AML initiation and
maintenance; 2) develop novel targeted therapies and immunotherapeutic approaches for AML based on
recurrent genomic alterations and leukemia stem-cell (LSC) specific markers; and 3) identify and validate the
mechanism of action, therapeutic efficacy, and predictors of response/resistance of mechanism-based therapies
for AML patients. To pursue these aims, we have assembled a multidisciplinary team with complementary
expertise in the clinical management of AML, cancer genetics, cancer epigenetics, functional genomics,
molecular pathology, biostatistics, computational biology, and multiplatform data integration. We will pursue
these aims through four projects, each addressing a different unmet need in the clinical management of AML.
Project 1 will elucidate genetic and epigenetic mechanisms of IDH inhibitor therapeutic resistance and perform
a clinical trial exploring the efficacy and safety of combining the FLT3 inhibitor gilteritinib with mutant selective
IDH1/2 inhibitors for FLT3/IDH-mutant AML. Project 2 will characterize the clinical, molecular, and biological
features of complex karyotype (CK) AML, for which there is no treatment, and validate a novel approach to
targeting CK AML via inhibition of the metabolic enzyme oxoglutarate dehydrogenase (OGDH). Project 3 will
evaluate a novel therapeutic approach for targeting common, poor prognosis spliceosomal-mutant AML subtypes
via inhibition of protein arginine methyltransferases in preclinical models and a phase I/II clinical trial. Project 4
will determine the safety and efficacy of a chimeric antigen receptor (CAR) T cell approach targeting a leukemia
stem cell-specific antigen while sparing normal hematopoietic stem cells, specifically, a fully humanized CD371
targeting CAR T cell platform bolstered by constitutive IL-18 secretion. All projects will be supported by the
Biospecimen, Biostatistics, Genomics, and Bioinformatics Shared Resource Cores, which will assist with
the preparation and analysis of human tissues and genomic, immune, and clinical data, and an Administrative
Core to ensure project integration. Finally, pilot projects in the Developmental Research Program and career
mentorship via the Career Enhancement Program are fully integrated into the SPORE to ensure that a future
generation of researchers is prepared to further advance our long-term objectives of enhancing therapy, reducing
the morbidity of treatments, and ultimately eliminating this disease as a cause of premature death

Grant Number: 5P50CA254838-05
NIH Institute/Center: NIH
Principal Investigator: Omar Abdel-Wahab