Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib

在最近的一项由联合领导人史密斯博士领导的临床试验中，卡博替尼（卡波; XL-184）显示出前所未有的骨 去势抵抗性前列腺癌（CRPC）男性的扫描反应。虽然反应明显， 患者最终进展，约30%的患者没有反应。卡波是一种多酪氨酸激酶， 对MET、VEGFR 2和RET具有最大活性的抑制剂，其与前列腺癌有关 (PCa)进展和骨微环境。使用临床前模型，我们发现一些PCas 在骨与软组织中对卡波显示出不同敏感性。此外，通过整合 测序，我们发现MET激活补偿了雄激素受体（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在预测肿瘤对卡波的敏感性和耐药性中的作用。所以 该提案的总体目标是利用正在进行的卡波临床试验， 体外和体内建模，

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