Dissecting the Determinants of IDH-mutant Gliomas Response to Mutant IDH Inhibitors

剖析 IDH 突变型胶质瘤对突变 IDH 抑制剂反应的决定因素

• 批准号: 10734393
• 负责人: Daniel P. Cahill
• 金额: $ 68.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734393
• 关键词: 19q; ATRX gene; Active Sites; Affect; Age; Arginine; Astrocytoma; Biological Assay; Cancer Etiology; Cell Cycle; Cell Survival; Cells; Cessation of life; Chromatin Structure; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Codon Nucleotides; Computer Analysis; Cues; DNA Sequence Alteration; Data; Development; Differentiation Therapy; Diffuse; Disease; Epigenetic Process; Gene Expression; Gene Mutation; Genes; Genetic; Genomics; Glioma; Growth; Heterozygote; Histidine; Human; In Vitro; Indolent; Infiltrative Growth; Isocitrate Dehydrogenase; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Normal Cell; Nuclear Pore Complex; Oncogenic; Organoids; PIK3CA gene; Patients; Persons; Population; Pre-Clinical Model; Process; Production; Public Health; Research Proposals; Resistance; Sampling; Specimen; Supporting Cell; TP53 gene; Testing; Tetracyclines; cancer cell; cohort; experimental study; genetic testing; in vitro Assay; in vivo; inhibitor; knock-down; mouse model; multiple omics; mutant; neoplastic; nerve stem cell; notch protein; novel; oligodendroglioma; patient subsets; programs; promoter; prototype; resistance gene; response; stem cells; therapeutic target; tumor; tumor growth; tumorigenesis; young adult

Abstract This proposal focuses on IDH-mutant gliomas, a leading cause of cancer-related death in people under 45 years old. IDH mutations result in profound distortions in metabolism, chromatin structure and the epigenetic control of gene expression. The oncogenicity of mutant IDH, together with its ubiquitous expression across malignant cells in IDH-mutant gliomas make it an attractive therapeutic target. However, we and others have found that the responses of IDH-mutant cancers to mutant IDH inhibitors (IDHi) are mixed: some tumors show growth inhibition in the presence of IDHi, while others do not. Clinically, studies in patients with progressive high-grade gliomas have shown scant signs of activity, but recent data showed signs of objective tumor responses in subset of patients with low-grade gliomas. The basis for this differential response in patients and in models is unknown. Our hypothesis, based on our preliminary data, is that IDHi may act as a differentiation therapy in subsets of glioma patients by inducing the differentiation of glioma progenitor cells towards mature glial lineages; we further hypothesize that both intrinsic and extrinsic factors will influence the capacity of glioma cells to respond to IDHi. To rigorously test our hypotheses, we propose (Aim 1) to perform single-cell multi-omics analysis in a cohort of IDH-mutant gliomas with and without clinical response to IDHi. We propose to profile IDHi-treated tumor specimen, and include matched pre- and on-treatment sample pairs. Leveraging novel human and murine low-grade glioma models, we then suggest to dissect how mutations associated with glioma progression (Aim 2) and how extrinsic microenvironmental factors (Aim 3) are affecting the tumor’s response to IDHi. Altogether, this co-PI R01 research proposal seeks to systematically dissect the neurodevelopmental, genetic and microenvironmental cues that determine IDH-mutant glioma’s response to IDHi throughout their progression.

摘要 这项提案的重点是IDH突变神经胶质瘤，这是癌症相关死亡的主要原因， 45岁了IDH突变导致代谢、染色质结构和细胞周期的严重扭曲。 基因表达的表观遗传控制。突变IDH的致癌性，连同其普遍存在的 在IDH突变型神经胶质瘤的恶性细胞中的表达使其成为有吸引力的治疗靶点。 然而，我们和其他人发现IDH突变型癌症对突变型IDH抑制剂的反应 IDHi（IDHi）是混合的：一些肿瘤在IDHi的存在下显示生长抑制，而另一些则没有。 临床上，对进行性高级别胶质瘤患者的研究显示活动迹象很少， 但最近的数据显示，在低级别胶质瘤患者的亚组中存在客观肿瘤反应的迹象。 患者和模型中这种差异反应的基础尚不清楚。我们的假设，基于 根据我们的初步数据，IDHi可能作为胶质瘤亚群的分化治疗， 通过诱导神经胶质瘤祖细胞向成熟神经胶质谱系分化来治疗患者; 我们进一步假设，内在和外在因素都会影响 胶质瘤细胞对IDHi的反应。为了严格检验我们的假设，我们建议（目标1）执行 IDH突变型胶质瘤队列中的单细胞多组学分析， IDHi.我们建议对IDHi治疗的肿瘤标本进行分析，并包括匹配的治疗前和治疗中的肿瘤标本。 样本对。利用新的人类和小鼠低级别胶质瘤模型，我们建议 剖析突变如何与胶质瘤进展相关（目标2）以及外源性 微环境因素（目标3）影响肿瘤对IDHi的反应。总的来说，这个合作伙伴 R 01研究提案旨在系统地剖析神经发育，遗传和 微环境线索，决定IDH突变胶质瘤的反应IDHi在他们的整个 进展