Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)

胃肠道间质瘤（GIST）的新疗法开发和耐药机制

• 批准号: 10932621
• 负责人: CRISTINA R ANTONESCU
• 金额: $ 24.67万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10932621
• 关键词: BRAF gene; Behavior; Biochemical; Biological Models; Biology; Biopsy Specimen; CRISPR interference; CRISPR/Cas technology; Cell Line; Chromatin Remodeling Factor; Citric Acid Cycle; Clinical; Clinical Trials; Clinical Trials Design; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; Custom; DDR1 gene; Defect; Dependence; Development; Disease; Drug resistance; ETV1 gene; Electron Transport; Epigenetic Process; Exhibits; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Generations; Genes; Genetic; Genomic approach; Goals; Growth; Human; Imatinib; In Vitro; Inter-tumoral heterogeneity; Interstitial Cell of Cajal; Investigation; Knockout Mice; Knowledge; LoxP-flanked allele; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mediating; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; NF1 mutation; Oncogenic; PDGFRA gene; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase Ib/II Trial; Pilot Projects; Population; Pre-Clinical Model; Proteins; RNA Interference; Receptor Protein-Tyrosine Kinases; Regulation; Resistance; Resistance development; Resources; Role; Sampling; Signal Induction; Signal Pathway; Signal Transduction; Soft tissue sarcoma; Specific qualifier value; Succinate Dehydrogenase; Technology; Therapeutic; Tumor Cell Line; Tumor Subtype; Tyrosine Kinase Inhibitor; cancer genomics; conditional knockout; design; driver mutation; epigenome; epigenomics; exome sequencing; genetic approach; in vitro Model; in vivo; in vivo Model; inhibitor; interdisciplinary approach; loss of function; mouse model; multidisciplinary; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; precursor cell; resistance mechanism; response; sarcoma; targeted sequencing; therapeutic development; therapeutic evaluation; therapeutic target; therapy resistant; tumor; tumor initiation; tumorigenesis; ubiquitin-protein ligase

RP-1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GIST ABSTRACT Gastrointestinal stromal tumor (GIST) represents one of the most prevalent sarcoma subtypes and is the most common mesenchymal neoplasm of the GI tract. Most GISTs harbor activating oncogenic “driver” mutations in receptor tyrosine kinases, e.g. KIT or PDGFRA. Among KIT/PDGFRA wild-type GISTs, the majority harbor loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle. KIT/PDGFRA-mutant and SDH-deficient GISTs represent molecularly distinct groups, with distinct clinical behaviors. We have recently identified ETV1 as a master regulator for the lineage specification and normal development of the GIST precursor cells, the interstitial cells of Cajal. Importantly, ETV1 is required for the growth and survival of imatinib-sensitive and -resistant GISTs in vitro and for tumor initiation and maintenance in vivo. We hypothesize ETV1 is a novel therapeutic target that is critical for the shared lineage-dependent survival of both imatinib-sensitive and -resistant GISTs. In this project, we propose a comprehensive study to understand the regulation of ETV1 protein stability, and to develop novel therapeutic strategies targeting ETV1 protein stability using various pre-clinical GIST models. In parallel, we will investigate clinical samples from prior and ongoing clinical trials designed to target ETV1 protein stability to better understand the molecular mechanisms of therapeutic resistance. Moreover, targeted sequencing using custom IMPACT panels will be used on these matched pre- and post-therapy biopsy samples from the on-going phase Ib/II trials using imatinib in combination with MEK162 to elucidate mechanism of drug resistance. This investigation will leverage comprehensive and multidisciplinary approaches, including biochemical, state-of-the-art genomics, and genetic approaches in in vitro and in vivo models as well as patient tumor samples derived from current GIST clinical trials. The therapeutic strategies identified here may benefit other ETV1-dependent malignancies. Lastly, since there are no in vitro and in vivo models for focused mechanistic and therapeutic investigation of SDH-deficient GISTs, we will generate cell line models through novel gene editing technology, such as CRISPR and CRISPRi, in established GIST cell lines as well as in human mesenchymal progenitor cells that are committed to the interstitial cells of Cajal lineage. We will also develop in vivo murine models of SDH-deficient GISTs for focused evaluation of therapeutics specifically targeting SDH deficiency that may benefit other SDH- deficient malignancies beyond GIST.

RP-1：GIST的新治疗药物开发和耐药机制 摘要 胃肠道间质瘤（GIST）是最常见的肉瘤亚型之一， 胃肠道最常见的间叶性肿瘤。大多数GIST携带激活致癌基因 受体酪氨酸激酶（例如KIT或PDGFRA）中的“驱动”突变。KIT/PDGFRA野生型 大多数GIST的线粒体琥珀酸脱氢酶功能缺失 (SDH)复合体是克雷布斯循环的一个组成部分。KIT/PDGFRA突变型和SDH缺陷型GIST 代表分子上不同的群体，具有不同的临床行为。我们最近发现 ETV 1作为GIST前体谱系特化和正常发育的主要调节因子 Cajal间质细胞重要的是，ETV 1是生长和生存所必需的， 伊马替尼敏感性和耐药性GIST的体外研究以及体内肿瘤起始和维持的研究。我们 假设ETV 1是一种新的治疗靶点，对于共享的谱系依赖性生存至关重要， 对伊马替尼敏感和耐药的GIST。在这个项目中，我们提出了一个全面的研究， 了解ETV 1蛋白稳定性的调节，并开发新的治疗策略 使用各种临床前GIST模型靶向ETV 1蛋白稳定性。与此同时，我们将调查 来自先前和正在进行的临床试验的临床样品，旨在使ETV 1蛋白稳定性更好 了解耐药性的分子机制。此外，靶向测序使用 定制IMPACT面板将用于这些匹配的治疗前和治疗后活检样本， 正在进行的Ib/II期试验，使用伊马替尼与MEK 162联合，以阐明 耐药性这项调查将利用全面和多学科的方法， 包括生物化学、最先进的基因组学和体外和体内模型中的遗传方法 以及来自当前GIST临床试验的患者肿瘤样品。mods的防治策略 这里确定的可能有益于其他ETV 1依赖性恶性肿瘤。最后，由于没有体外和 在体内模型的重点机制和治疗调查的SDH缺陷GIST，我们将 通过新型基因编辑技术（如CRISPR和CRISPRi）生成细胞系模型， 在已建立的GIST细胞系中以及在定向于GIST的人间充质祖细胞中， Cajal系间质细胞。我们还将开发SDH缺陷型GIST的体内小鼠模型， 对可能有益于其他SDH的SDH缺乏症的治疗方法进行集中评价， GIST以外的恶性肿瘤。