The Memorial Sloan Kettering Cancer Center SPORE in Leukemia

总体摘要 尽管近年来急性髓细胞白血病（AML）的治疗取得了进展，但大多数AML患者复发 治疗后，成人AML患者的总体五年生存率仍为25- 29%。因此，紧急 需要改进AML患者的治疗。白血病MSK孢子将利用集体努力 为几种复发性分子生物学疾病开发有效的靶向治疗和免疫治疗方法， AML亚型，包括一些完全缺乏治疗选择的亚型。的总体翻译目标 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， 维持; 2）开发新的AML靶向治疗和免疫治疗方法， 复发性基因组改变和白血病干细胞（LSC）特异性标志物;以及3）鉴定和验证 作用机制、疗效和基于机制治疗的反应/耐药预测因子 对于AML患者。为了实现这些目标，我们组建了一个多学科团队， 在AML临床管理、癌症遗传学、癌症表观遗传学、功能基因组学、 分子病理学、生物统计学、计算生物学和多平台数据集成。我们将奉行 通过四个项目实现这些目标，每个项目解决AML临床管理中未满足的不同需求。 项目1将阐明IDH抑制剂治疗抗性的遗传和表观遗传机制，并进行 一项探索FLT 3抑制剂gilteritinib与突变选择性 用于FLT 3/IDH突变AML的IDH 1/2抑制剂。项目2将描述临床、分子和生物学特征， 复杂核型（CK）AML的特征，对此没有治疗方法，并验证了一种新的方法， 通过抑制代谢酶酮戊二酸脱氢酶（OGDH）靶向CK AML。项目3将 评估一种针对常见的、预后不良的剪接体突变型AML亚型的新型治疗方法 通过在临床前模型和I/II期临床试验中抑制蛋白质精氨酸甲基转移酶。项目4 将确定靶向白血病的嵌合抗原受体（CAR）T细胞方法的安全性和有效性 干细胞特异性抗原，同时保留正常造血干细胞，具体地，完全人源化的CD 371 靶向CAR T细胞平台，由组成型IL-18分泌支持。所有项目将得到 生物标本、生物统计学、基因组学和生物信息学共享资源核心， 人类组织和基因组，免疫和临床数据的制备和分析，以及行政管理 核心是确保项目的整合。最后，发展研究计划和职业生涯中的试点项目 通过职业提升计划的指导完全融入了SPORE，以确保未来 一代研究人员准备进一步推进我们的长期目标，即加强治疗，减少 治疗的发病率，并最终消除这种疾病作为过早死亡的原因

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