The Memorial Sloan Kettering Cancer Center SPORE in Leukemia

纪念斯隆凯特琳癌症中心 SPORE 白血病

• 批准号: 10474261
• 负责人: Omar Abdel-Wahab
• 金额: $ 218.64万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474261
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Antigens; Area; Bioinformatics Shared Resource; Biological; Biological Models; Biometry; Cessation of life; Classification; Clinic; Clinical; Clinical Data; Clinical Investigator; Clinical Management; Clinical Trials; Collaborations; Complex; Computational Biology; DNA Sequence Alteration; Development; Disease; Dysmyelopoietic Syndromes; Eastern Cooperative Oncology Group; Ensure; Enzymes; Epigenetic Process; Evaluation; FLT3 gene; FLT3 inhibitor; Future Generations; Genetic; Genomic approach; Genomics; Goals; Hematopoietic Stem Cell Research; Hematopoietic stem cells; Human; Immune; Immune Targeting; Immunotherapeutic agent; Immunotherapy; Incidence; Industry; Institutes; Institution; Interleukin-18; Karyotype; Ketoglutarate Dehydrogenase Complex; Lead; Maintenance; Malignant Neoplasms; Medical; Memorial Sloan-Kettering Cancer Center; Mentorship; Metabolic; Molecular; Molecular Abnormality; Molecular Target; Morbidity - disease rate; Mutation; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Pharmacotherapy; Phase I/II Clinical Trial; Pilot Projects; Pre-Clinical Model; Preparation; Prognosis; Protein Inhibition; Protein-Arginine N-Methyltransferase; RNA Splicing; Recurrence; Research; Research Personnel; Research Project Grants; Resistance; Resource Sharing; Risk; Safety; Sampling; Southwest Oncology Group; Survival Rate; TP53-mutant acute myeloid leukemia; Therapeutic; Therapy-Related Acute Myeloid Leukemia; Translating; Translational Research; Treatment Efficacy; United States Food and Drug Administration; Universities; base; cancer genetics; career; chimeric antigen receptor T cells; collaborative approach; data integration; early phase clinical trial; effective therapy; functional genomics; genomic biomarker; high risk; human tissue; improved; improved outcome; inhibitor; inhibitor therapy; innovation; insight; leukemia; leukemia treatment; leukemic stem cell; medical schools; molecular pathology; molecular subtypes; molecular targeted therapies; multidisciplinary; mutant; new therapeutic target; novel; novel marker; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; predicting response; premature; programs; relapse patients; resistance mechanism; response biomarker; stem cell biomarkers; targeted treatment; therapeutic target; therapy resistant; translational potential; treatment response; tumor

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

整体的抽象