TY - JOUR
T1 - Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer
AU - Varkaris, Andreas
AU - Corn, Paul G.
AU - Parikh, Nila U.
AU - Efstathiou, Eleni
AU - Song, Jian H.
AU - Lee, Yu Chen
AU - Aparicio, Ana
AU - Hoang, Anh G.
AU - Gaur, Sanchaika
AU - Thorpe, Lynnelle
AU - Maity, Sankar N.
AU - Eli, Menashe Bar
AU - Czerniak, Bogdan A.
AU - Shao, Yiping
AU - Alauddin, Mian
AU - Lin, Sue Hwa
AU - Logothetis, Christopher J.
AU - Gallick, Gary E.
N1 - Funding Information:
The authors thank Dr. William Benedict for the expert scientific suggestions and critical readingof the article. They also thank Katerina Kaffesand Michel Keith for NaF-18 PET scan and μCT data acquisition and analysis. Finally, they thank Dana Aftab (Exelixis, Inc.) for providing cabozantinib for preclinical studies. This work is supported by the National Cancer Institute (NCI) Grant No. P50 CA140388; a Prostate Cancer Foundation (PCF) Challenge award; a PCF Creativity Award; and The University of Texas MD Anderson Prostate Cancer Moon Shots Program (C.J. Logothetis and G.E. Gallick); a PCF Young Investigator Award (A. Varkaris); a PCF Career Development Award (E. Efstathiou), a UT Health Innovation for Cancer Prevention Research Pre-doctoral Fellowship, The University of Texas School of Public Health-Cancer Prevention and Research Institute of Texas grant #RP101503 (S. Gaur), Cancer Prevention and Research Institute of Texas grant #RPO150282 (G.E. Gallick) and Cancer Center Support Grant (CA16672), and the Solon Scott III donor funds (P.G. Corn). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
Copyright © 2015 AACR.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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 pMETpositive 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.
AB - 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 pMETpositive 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.
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U2 - 10.1158/1078-0432.CCR-15-0235
DO - 10.1158/1078-0432.CCR-15-0235
M3 - Article
C2 - 26272062
AN - SCOPUS:84954483093
SN - 1078-0432
VL - 22
SP - 107
EP - 121
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -