Data from Cabozantinib Inhibits Prostate Cancer Growth and Prevents Tumor-Induced Bone Lesions

Abstract

<div>Abstract<p><b>Purpose:</b> Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.</p><p><b>Experimental Design:</b> Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. <i>In vitro</i> studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.</p><p><b>Results:</b> Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis <i>in vitro</i> and <i>in vivo</i> and inhibited cell invasion <i>in vitro</i>. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production <i>in vitro</i> that was reflected <i>in vivo</i>. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.</p><p><b>Conclusion:</b> These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy. <i>Clin Cancer Res; 20(3); 617–30. ©2013 AACR</i>.</p></div>