The Memorial Sloan Kettering Cancer Center SPORE in Leukemia

纪念斯隆凯特琳癌症中心 SPORE 白血病

基本信息

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
项目类别：
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

项目摘要

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

总体抽象尽管最近在治疗急性髓样白血病（AML）方面取得了进步，大多数AML患者复发在治疗和AML成年人的总体五年生存率之后，仍为25-29％。因此，紧急需要改善AML患者的治疗。白血病的MSK孢子将利用集体努力开发有效的靶向疗法和几种复发分子的免疫治疗方法 AML的亚型，包括一些完全缺乏治疗选择的亚型。总体翻译目的白血病中的MSK孢子是1）询问AML启动所需的遗传和分子途径维护; 2）基于AML开发新颖的靶向疗法和免疫治疗方法复发性基因组改变和白血病干细胞（LSC）特定标记； 3）识别和验证基于机制的治疗的作用机理，治疗功效和预测因素适用于AML患者。为了追求这些目标，我们已经组建了一个多学科团队在AML，癌症遗传学，癌症表观遗传学，功能基因组学的临床管理方面的专业知识，分子病理学，生物统计学，计算生物学和乘法数据整合。我们将追求这些目标是通过四个项目，每个项目都满足了AML临床管理的不同需求。项目1将阐明IDH抑制剂治疗性的遗传和表观遗传机制并进行一项临床试验，探索将FLT3抑制剂吉尔特替尼与突变体选择性相结合的功效和安全性 FLT3/IDH突变AML的IDH1/2抑制剂。项目2将表征临床，分子和生物学复杂的核型（CK）AML的特征，没有治疗，并验证一种新的方法靶向CK AML通过抑制代谢酶氧化酶脱氢酶（OGDH）。项目3威尔评估一种新型的治疗方法，用于靶向常见，预后不良的剪接体突变剂AML亚型通过抑制临床前模型中的蛋白精氨酸甲基转移酶和I/II期临床试验。项目4 将确定针对白血病的嵌合抗原受体（CAR）T细胞方法的安全性和功效干细胞特异性抗原在保留正常造血干细胞时，特别是完全人性化的CD371 靶向CAR T细胞平台由本构IL-18分泌增强。所有项目将由生物体系，生物统计学，基因组学和生物信息学共享资源核心，这将有助于实现人体组织的制备和分析以及基因组，免疫和临床数据以及行政确保项目集成的核心。最后，发展研究计划和职业的试点项目通过职业增强计划的指导已完全集成到孢子中，以确保未来生成研究人员准备进一步促进我们增强治疗的长期目标，减少治疗治疗的发病率，并最终消除这种疾病作为过早死亡的原因