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：胃肠道间质瘤的新疗法开发和治疗耐药机制抽象的胃肠道间质瘤 (GIST) 是最常见的肉瘤亚型之一，胃肠道最常见的间叶性肿瘤，大多数胃肠道间质瘤都具有激活性致癌基因。受体酪氨酸激酶的“驱动”突变，例如 KIT/PDGFRA 野生型。大多数胃肠道间质瘤都存在线粒体琥珀酸脱氢酶功能丧失的缺陷 (SDH) 复合物，KIT/PDGFRA 突变型和 SDH 缺陷型 GIST 的一个组成部分。我们最近发现了分子上不同的群体，具有不同的临床行为。 ETV1 作为 GIST 前体谱系规范和正常发育的主要调节因子重要的是，ETV1 是 Cajal 细胞的生长和存活所必需的。体外对伊马替尼敏感和耐药的 GIST 以及体内肿瘤的引发和维持。被破坏的 ETV1 是一种新的治疗靶点，对于共同的谱系依赖性生存至关重要在这个项目中，我们提出了一项全面的研究来研究对伊马替尼敏感和耐药的胃肠道间质瘤。了解 ETV1 蛋白稳定性的调节，并开发新的治疗策略同时，我们将使用各种临床前 GIST 模型来研究 ETV1 蛋白的稳定性。来自先前和正在进行的临床试验的临床样本，旨在更好地靶向 ETV1 蛋白稳定性此外，使用靶向测序了解治疗耐药性的分子机制。定制的 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，使用伊马替尼联合 MEK162 来阐明其机制这项调查将利用综合性和多学科的方法，包括生物化学、最先进的基因组学以及体外和体内模型的遗传方法以及来自当前 GIST 临床试验的患者肿瘤样本的治疗策略。最后，由于没有体外和体外试验，因此此处确定的可能有益于其他 ETV1 依赖性恶性肿瘤。用于 SDH 缺陷 GIST 的集中机制和治疗研究的体内模型，我们将通过新型基因编辑技术（例如 CRISPR 和 CRISPRi）生成细胞系模型已建立的 GIST 细胞系以及人类间充质祖细胞致力于我们还将开发 SDH 缺陷 GIST 的体内小鼠模型。重点评估专门针对 SDH 缺乏症的治疗方法，这些治疗方法可能有益于其他 SDH- 胃肠道间质瘤（GIST）以外的缺陷性恶性肿瘤。