Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib

激酶抑制剂卡博替尼的敏感性和耐药性机制

基本信息

批准号：
8788150
负责人：
Evan T Keller
金额：
$ 24.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-11 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788150
关键词：
Androgen Receptor Biopsy Bone Tissue Cell model Clinical Clinical Trials Clinical effectiveness Diffusion Magnetic Resonance Imaging Epidermal Growth Factor Receptor Fracture Freezing Genomics Genotype Goals In Vitro Lead Malignant Neoplasms Malignant neoplasm of prostate Mediator of activation protein Metastatic Neoplasm to the Bone Methods PC3 cell line Pain Pathway interactions Patients Phenotype Pre-Clinical Model Receptor Signaling Research Personnel Resistance Role Signal Transduction Site Testing Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors bone bone imaging castration resistant prostate cancer improved in vivo Model kinase inhibitor men novel pre-clinical resistance mechanism response soft tissue tissue culture transcriptome sequencing transcriptomics tumor tumor microenvironment tumor progression

项目摘要

In a recent clinical trial led by Co-Leader Dr. Smith, Cabozantinib (CABO; XL-184) showed unprecedented bone scan responses in men with castration-resistant prostate cancer (CRPC). Although marked responses are seen, patients eventually progress and about 30% of patients do not respond. CABO is a multi-tyrosine kinase inhibitor with greatest activity against MET, VEGFR2 and RET, which have been implicated in prostate cancer (PCa) progression and the bone microenvironment. Using preclinical models we have found that some PCas show differential sensitivity to CABO when in bone versus soft tissue. Furthermore, through integrative sequencing, we have found that MET activation compensates for loss of androgen receptor (AR) signaling in CRPC. These clinical and pre-clinical results provide a compelling rationale for studying the role of both the tumor itself and the tumor microenvironment in predicting tumor sensitivity and resistance to CABO. Hence, the overarching goal of this proposal is to leverage an ongoing investigator-initiated clinical trial of CABO and use in vitro and in vivo modeling to

在最近由联合负责人 Smith 博士领导的一项临床试验中，卡博替尼 (CABO; XL-184) 显示出前所未有的骨质疏松患有去势抵抗性前列腺癌（CRPC）的男性的扫描反应。尽管看到了明显的反应，患者最终会出现进展，大约 30% 的患者没有反应。 CABO是一种多酪氨酸激酶对与前列腺癌有关的 MET、VEGFR2 和 RET 具有最强活性的抑制剂 (PCa) 进展和骨微环境。使用临床前模型，我们发现一些 PCas 在骨组织和软组织中对 CABO 表现出不同的敏感性。此外，通过综合测序后，我们发现 MET 激活可以补偿雄激素受体 (AR) 信号传导的损失 CRPC。这些临床和临床前结果为研究这两种药物的作用提供了令人信服的理由。肿瘤本身和肿瘤微环境可以预测肿瘤对 CABO 的敏感性和耐药性。因此，该提案的总体目标是利用正在进行的研究者发起的 CABO 临床试验并将其用于体外和体内建模