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
Prostate cancer is the most common non-skin cancer of men. When prostate cancer progresses, over 80% of men develop bone metastases which cause fracture and pain. Cabozantanib (CABO) treatment results in marked regression of prostate cancer however it is not effective in all patients and resistance eventually develops. Defining mechanisms of resistance will lead us to improve clinical effectiveness of CABO or determine which patients would or would not benefit from CABO treatment.