P1 - Molecular Mechanisms of KIT Signaling and Imatinib Resistance in GIST

P1 - GIST 中 KIT 信号传导和伊马替尼耐药的分子机制

基本信息

批准号：
7976097
负责人：
CRISTINA R ANTONESCU
金额：
$ 124.89万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7976097
关键词：
1-Phosphatidylinositol 3-Kinase Alleles Basic Science Binding Biochemical Candidate Disease Gene Cell Culture Techniques Cells Childhood Clinical Deletion Mutation Detection Disease Doctor of Philosophy Drug resistance Evaluation Event Gametogenesis Gastrointestinal Stromal Tumors Generations Genes Genetic Genomics Genotype Guidelines Hematopoiesis Human Hyperplasia Imatinib Imatinib mesylate In complete remission Inherited Integrins Intervention Investigation Knock-in Mouse Modeling Molecular Molecular Conformation Molecular Profiling Mus Mutagenesis Mutation Oncogenic PDGFRA gene Pathogenesis Pathway Analysis Pathway interactions Patients Pattern Phosphotransferases Proteins RNA Sequences Receptor Protein-Tyrosine Kinases Receptor Signaling Resistance Role Screening procedure Signal Pathway Signal Transduction Signaling Pathway Gene Site Solid Stable Disease Syndrome System Testing Therapeutic Tumor Cell Line Tyrosine Kinase Inhibitor base cancer therapy drug sensitivity gain of function mutation gastrointestinal genome-wide high throughput screening human FRAP1 protein human PDGFA protein in vivo inhibitor/antagonist interest interstitial kinase inhibitor mouse genome mouse model mutant nodal myocyte novel novel therapeutics partial response pre-clinical prototype resistance mechanism therapeutic target tool treatment strategy tumorigenesis

项目摘要

Gastrointestinal stromal tumors (GISTs) are driven by KIT receptor tyrosine kinase, and most have gain-offunction mutations In KIT or occasionally in PDGFRA. Imatinib, which inhibits KIT and PDGFRA, produces a partial response or stable disease in 80% of GIST patients, but complete response is rare. Moreover, about half of the patients who benefit from imatinib treatment eventually develop drug resistance, and few other treatments are available. A common mechanism of acquired resistance is second-site KIT mutations. We propose 4 overall objectives. (1) Use genomic approaches to identify alternative signaling pathways in GIST lacking KIT or PDGFRA mutations and in imatinib-resistant GIST lacking an Identifiable mechanism of resistance. Candidate genes will be validated and pathway analysis applied to identify potential targets for therapy. (2) Identify mutations that confer resistance to imatinib or to other kinase inhibitors so as to develop guidelines for genotype-tailored therapy. (3) Investigate novel pharmacological intervention strategies in vivo in the KitV558del/+ mouse, a model of imatinib-responsive GIST. (4) Develop imatinib-resistant mouse models and apply them for the evaluation of new treatment strategies for imatinibresistant GIST. The treatment strategies to be tested are second^generation tyrosine kinase inhibitors alone and In combination with inhibitors of downstream effectors of KIT, targeting PI 3-kinase, integrin, and STAT signaling. By elucidating the pathways active in imatinib-resistant GIST and by preclinical investigations, we aim to find new therapeutic options for patients with Imatinib-resistant GIST.

胃肠道间质瘤 (GIST) 由 KIT 受体酪氨酸激酶驱动，大多数具有功能获得性 KIT 突变或偶尔出现 PDGFRA 突变。伊马替尼可抑制 KIT 和 PDGFRA，产生 80% 的 GIST 患者部分缓解或病情稳定，但完全缓解的情况很少见。此外，关于受益于伊马替尼治疗的一半患者最终会产生耐药性，而其他患者则很少可以进行治疗。获得性耐药的一个常见机制是第二位点 KIT 突变。我们提出4个总体目标。 (1) 使用基因组方法来识别替代信号传导缺乏 KIT 或 PDGFRA 突变的 GIST 以及缺乏可识别的伊马替尼耐药 GIST 的通路抵抗机制。将验证候选基因并应用途径分析来识别治疗的潜在目标。 (2) 识别对伊马替尼或其他激酶产生耐药性的突变抑制剂，以便制定基因型定制治疗的指南。 (3) 研究新药理 KitV558del/+ 小鼠（伊马替尼反应性 GIST 模型）的体内干预策略。 (4) 开发伊马替尼耐药小鼠模型并应用于伊马替尼耐药新治疗策略的评估要旨。待测试的治疗策略是单独使用第二代酪氨酸激酶抑制剂与 KIT 下游效应子抑制剂联合，靶向 PI 3-激酶、整合素和 STAT 发信号。通过阐明伊马替尼耐药 GIST 中的活跃通路和临床前研究，我们旨在为伊马替尼耐药的胃肠道间质瘤患者寻找新的治疗选择。