Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib

在最近由联合负责人史密斯博士领导的一项临床试验中，Cabozantinib(Cabo；XL-184)显示出前所未有的骨骼 抗去势前列腺癌(CRPC)患者的扫描反应。尽管可以看到标记的响应， 患者最终会进步，大约30%的患者没有反应。CABO是一种多酪氨酸激酶 抑制MET、VEGFR2和RET活性最高的抑制剂，它们与前列腺癌有关 (PCA)进展与骨骼微环境。使用临床前模型，我们发现一些PCAS 在骨骼和软组织中表现出对CABO的鉴别敏感性。此外，通过一体化的 测序，我们发现MET的激活可以补偿雄激素受体(AR)信号的丢失 CRPC。这些临床和临床前的结果为研究两者的作用提供了令人信服的理由 肿瘤本身和肿瘤微环境在预测肿瘤对CABO敏感性和耐药性中的作用。因此， 这项提案的总体目标是利用正在进行的由研究人员发起的CABO临床试验，并在 体外和体内建模以

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