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.

胃肠道间质肿瘤（GIST）由试剂盒受体酪氨酸激酶驱动，大多数具有增益后套件中的突变或偶尔在PDGFRA中。抑制套件和PDGFRA的伊马替尼产生一个在80％的GIST患者中，部分反应或稳定疾病，但完全反应很少。而且，关于一半从伊马替尼治疗中受益的患者最终会产生耐药性，而其他很少的患者可以治疗。获得的电阻的常见机制是第二站点套件突变。我们提出了4个总体目标。（1）使用基因组方法识别替代信号传导 GIST缺乏套件或PDGFRA突变的途径以及抗伊马替尼的抗性要点缺乏可识别的抗性机制。候选基因将得到验证，并应用途径分析以识别治疗的潜在靶标。（2）确定赋予对伊马替尼或其他激酶抗性的突变抑制剂以制定基因型量治疗的指南。（3）研究新型药理 kITV558DEL/+鼠标的干预策略，伊马替尼反应性要点的模型。（4）发展伊马替尼的鼠标模型，并将其应用于评估imatinibresistant的新治疗策略要旨。要测试的治疗策略仅是第二代酪氨酸激酶抑制剂并结合套件下游效应子的抑制剂，靶向PI 3-激酶，整合素和STAT 信号。通过阐明抗伊马替尼抗性的途径和临床前研究的途径，我们旨在为抗伊马替尼抗性的患者找到新的治疗选择。