CLINCAL CANCER RESEARCH

Varkaris A, Corn PG, Parikh NU, Efstathiou E, Song JH, Lee YC, Aparicio A, Hoang AG, Gaur S, Thorpe L, Maity SN, Bar Eli M, Czerniak BA, Shao Y, Alauddin M, Lin SH, Logothetis CJ and Gallick GE.

Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2016;22:107-21.

DOI: 10.1158/1078-0432.CCR-15-0235

Abstract

Purpose: We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy.

Experimental Design: In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined.

Results: In responsive patients and PDX, islets of viable pMET-positive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts.

Conclusions: Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents. Clin Cancer Res; 22(1); 107–21. ©2015 AACR.

Translational Relevance

By integrating clinical and murine investigations, mechanisms of action of therapeutic agents can be linked to clinical benefit and development of resistance. Using this approach, we demonstrate that the clinical activity of cabozantinib, a multitargeted MET/VEGFR2 inhibitor, is due primarily to inhibition of angiogenesis and bone turnover. We show that MET-positive tumor cells are present in both bone biopsies from responsive patients and patient-derived xenografts, and from the latter, that MET expression does not affect activity of cabozantinib. Furthermore, we demonstrate that vascular heterogeneity represents one source of primary resistance to cabozantinib, and induction of FGFR1 expression in tumor cells is a potential mechanism of acquired therapy resistance. Finally, we show that dosing schedule affects the efficacy of microenvironment targeting agents, such as cabozantinib. Our results provide general insights into targets and mechanisms of resistance that should dictate future development of clinical trials with targeted therapies.