Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer

• Published in: Clinical cancer research Vol. 22; no. 1; pp. 107 - 121
• Main Authors: Varkaris, Andreas, Corn, Paul G, Parikh, Nila U, Efstathiou, Eleni, Song, Jian H, Lee, Yu-Chen, Aparicio, Ana, Hoang, Anh G, Gaur, Sanchaika, Thorpe, Lynnelle, Maity, Sankar N, Bar Eli, Menashe, Czerniak, Bogdan A, Shao, Yiping, Alauddin, Mian, Lin, Sue-Hwa, Logothetis, Christopher J, Gallick, Gary E
• Format: Journal Article
• Language: English
• Published: United States 01.01.2016
• Subjects: Anilides - pharmacology; Anilides - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Bone Neoplasms - diagnosis; Bone Neoplasms - secondary; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Male; Mice; Multicenter Studies as Topic; Neoplasm Staging; Phosphorylation; Positron-Emission Tomography; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Signal Transduction - drug effects; Treatment Outcome; Tumor Burden - drug effects; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-0235

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. 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. 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. 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.