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

基本信息

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
项目类别：
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

项目摘要

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：要点的新型治疗性发展和治疗性抗性机制抽象的胃肠道肿瘤（GIST）代表最普遍的肉瘤亚型之一，IS 胃肠道最常见的间质肿瘤。大多数GISTS港都激活致癌受体酪氨酸激酶的“驱动器”突变，例如套件或PDGFRA。在Kit/PDGFRA野生型中 GIST，大多数港口的功能丧失缺陷在线粒体琥珀酸酯脱氢酶中（SDH）复合物，这是克雷布斯循环的组成部分。套件/PDGFRA突变和SDH缺乏的要点代表具有不同临床行为的分子不同组。我们最近确定了 ETV1作为谱系前体的谱系规范和正常发展的主调节器细胞，Cajal的间质细胞。重要的是，ETV1的生长和生存需要伊马替尼对体外和体内肿瘤的启动和维持的敏感性和耐药性。我们假设ETV1是一个新型的热目标，对于共享谱系依赖性生存至关重要伊马替尼对伊替尼的敏感性和抗性的要点。在这个项目中，我们提出了一项全面的研究了解ETV1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ETV1蛋白稳定性。同时，我们将调查旨在针对ETV1蛋白稳定性的临床和正在进行的临床试验的临床样本了解热电阻的分子机制。此外，使用针对的测序使用自定义影响面板将用于这些匹配的术前和后治疗后的活检样本使用伊马替尼与MEK162结合的持续IB/II期试验，以阐明耐药性。这项投资将利用全面和多学科的方法，包括生化，最先进的基因组学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。治疗策略此处确定的可能会受益于其他依赖ETV1的恶性肿瘤。最后，因为没有体外和体内模型，用于对SDH缺陷的GIST的重点机理和治疗研究，我们将通过新颖的基因编辑技术（例如CRISPR和CRISPRI）生成细胞系模型，建立的GIST细胞系以及在人类间充质祖细胞中，致力于 Cajal谱系的间质细胞。我们还将开发出缺乏SDH的GIST的体内鼠模型专门针对SDH缺乏症的治疗剂的重点评估，这可能使其他SDH-受益防御性恶性肿瘤超出了要点。