权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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: GIST治疗耐药的新疗法发展和机制