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

总体摘要尽管急性髓系白血病 (AML) 的治疗最近取得了进展，但大多数 AML 患者都会复发治疗后，成人 AML 的总体五年生存率仍为 25-29%。因此，紧急仍然需要改进 AML 患者的治疗。 MSK SPORE 治疗白血病将利用集体努力为几种复发性分子肿瘤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。总体翻译目标 MSK SPORE 在白血病中的作用是 1) 询问 AML 启动所需的遗传和分子途径，以及维护; 2）基于AML开发新的靶向治疗和免疫治疗方法反复发生的基因组改变和白血病干细胞（LSC）特异性标记； 3) 识别并验证基于机制的治疗的作用机制、治疗效果和反应/耐药的预测因子对于 AML 患者。为了实现这些目标，我们组建了一支具有互补性的多学科团队 AML临床管理、癌症遗传学、癌症表观遗传学、功能基因组学的专业知识，分子病理学、生物统计学、计算生物学和多平台数据集成。我们将追求这些目标通过四个项目实现，每个项目都解决 AML 临床管理中不同的未满足需求。项目1将阐明IDH抑制剂治疗耐药性的遗传和表观遗传机制并进行一项探索FLT3抑制剂gilteritinib与突变选择性结合的有效性和安全性的临床试验用于 FLT3/IDH 突变 AML 的 IDH1/2 抑制剂。项目 2 将表征临床、分子和生物学复杂核型 (CK) AML 的特征，目前尚无治疗方法，并验证一种新方法通过抑制代谢酶氧化戊二酸脱氢酶 (OGDH) 来靶向 CK AML。项目3将评估一种针对常见、预后不良的剪接体突变 AML 亚型的新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 将确定针对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，特别是完全人源化的 CD371 由组成型 IL-18 分泌支持的靶向 CAR T 细胞平台。所有项目都将得到以下机构的支持生物样本、生物统计学、基因组学和生物信息学共享资源核心，这将有助于人体组织和基因组、免疫和临床数据的准备和分析，以及行政管理确保项目集成的核心。最后，发展研究计划和职业中的试点项目通过职业提升计划进行的指导已完全融入 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