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Principal Investigator: Omar Abdel-Wahab
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $2,256,925
Funding agency: National Cancer Institute
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
Terms: <2-Keto-4-Hydroxyglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase Complex><21+ years old><AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Adult><Adult Human><Antigens><Area><Arginine Methylase><Bioinformatics Shared Resource><Biologic Models><Biological><Biological Models><Biometrics><Biometry><Biostatistics><Blood Precursor Cell><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><Cancers><Cessation of life><Chromosomal, Gene, or Protein Abnormality><Classification><Clinic><Clinical><Clinical Data><Clinical Investigator><Clinical Management><Clinical Trials><Collaborations><Complex><Computational Biology><Cytogenetic or Molecular Genetic Abnormality><DNA Alteration><DNA Sequence Alteration><DNA mutation><Death><Development><Disease><Disorder><Drug Therapy><Dysmyelopoietic Syndromes><ECOG><Eastern Cooperative Oncology Group><Ensure><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><FLK2><FLT3><FLT3 gene><FLT3 inhibitor><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><Food and Drug Administration><Future Generations><Genetic><Genetic Abnormality><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genomic approach><Genomics><Goals><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Histone (Arginine) Methyltransferase><Human><IFN-Gamma-Inducing Factor Gene><IFN-gamma-Inducing Factor><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-18><IL-18 Gene><IL-1g><IL-1g Gene><IL18><IL18 Protein><IL18 gene><IL1F4><IL1F4 Gene><Immune><Immune Targeting><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><Incidence><Industry><Institution><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Investigators><Karyotype><Ketoglutarate Dehydrogenase Complex><Lead><Leukemic progenitor and stem cell><MGC12320><MGC12320 Gene><MSKCC><Maintenance><Malignant Neoplasms><Malignant Tumor><Medical><Memorial Sloan-Kettering Cancer Center><Mentorship><Metabolic><Model System><Modern Man><Molecular><Molecular Abnormality><Molecular Target><Morbidity><Morbidity - disease rate><Mutation><Myelin Basic Protein (Arginine) Methyltransferase><Myelodysplastic Disease><Myelodysplastic Syndromes><Oxoglutarate Dehydrogenase><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pharmacotherapy><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Pilot Projects><Pre-Clinical Model><Preclinical Models><Preparation><Prognosis><Protein Arginine Methyltransferase><Protein Inhibition><Protein Methylase I><Protein Methyltransferase I><Protein-Arginine N-Methyltransferase><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Splicing><Recurrence><Recurrent><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Reproduction spores><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resistance><Resource Sharing><Risk><STK-1 kinase><STK1><SWOG><Safety><Sampling><Sequence Alteration><Smoldering Leukemia><Southwest Oncology Group><Spliceosomes><Splicing><Spores><Stem Cell Tyrosine Kinase 1><Survival Rate><Systematics><T cells for CAR><TP53 mutated AML><TP53 mutated acute myeloid leukemia><TP53-mutant AML><TP53-mutant acute myeloid leukemia><Therapeutic><Therapy-Related Acute Myeloid Leukemia><Translating><Translational Research><Translational Science><Treatment Efficacy><Treatment-Related AML><Treatment-Related Acute Myelocytic Leukemia><Treatment-Related Acute Myelogenous Leukemia><Treatment-related Acute Myeloid Leukemia><USFDA><United States Food and Drug Administration><Universities><acute granulocytic leukemia><acute myeloid leukemia><adulthood><adverse consequence><adverse outcome><alpha-Ketoglutarate Dehydrogenase><alpha-Ketoglutarate Dehydrogenase Complex><bio-informatics shared resource><biologic><biomarker identification><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cancer genetics><career><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><collaborative approach><computer biology><data driven platform><data integration><data platform><developmental><drug treatment><early clinical trial><early phase clinical trial><effective therapy><effective treatment><epigenetically><expression subtypes><fetal liver kinase-2><fetal liver kinase-3><functional genomics><genome mutation><genomic alteration><genomic biomarker><genomic effort><genomic marker><genomic strategy><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high risk><human tissue><identification of biomarkers><identification of new biomarkers><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic therapeutics><immunotherapeutics><immunotherapy agent><improved><improved outcome><inhibit protein><inhibit proteins><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><innovate><innovation><innovative><insight><intervention efficacy><karyogram><leukemia><leukemia treatment><leukemic progenitor><leukemic stem cell><leukemic therapy><malignancy><marker identification><medical college><medical schools><molecular aberrations><molecular pathology><molecular sub-types><molecular subsets><molecular subtypes><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><multidisciplinary><mutant><myelodysplasia><neoplasm/cancer><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new marker><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel biomarker><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><pathway><patient oriented outcomes><pharmaceutical><pilot study><pre-clinical><pre-clinical study><preclinical><preclinical study><predict responsiveness><predicting response><premature><prematurity><preparations><progenitor cell markers><progenitor markers><progenitor stem cell markers><programs><protein inhibitions><relapse patients><resistance mechanism><resistance to therapy><resistant><resistant mechanism><resistant to therapy><response biomarker><response markers><response to therapy><response to treatment><school of medicine><stem cell biomarkers><stem cell markers><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic resistance><therapeutic response><therapeutic target><therapy efficacy><therapy resistant><therapy response><translation research><translational investigation><translational opportunities><translational potential><treatment resistance><treatment response><treatment responsiveness><tumor>