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

Abstract

Purpose Cabozantinib, an orally available multi-tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor 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 anti-tumor effect, an indirect effect through modulating bone, or both. Experimental Design Using human prostate cancer xenograft studies in mice we determined cabozantinib's impact on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (1) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability and MET and (2) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2. Results 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 in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro, that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively. Conclusion These data indicate that cabozantinib has direct anti-tumor activity; and that its ability to modulate osteoblast activity may contribute to its anti-tumor efficacy.

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

“…It has been reported that cabozantinib suppressed cell migration and invasion in various types of tumor cells (23,35). Consistently, our results showed that cabozantinib inhibited HGF-stimulated migration and invasion in HCC cell lines.…”

Targeted therapies in advanced differentiated thyroid cancer

“…While 5 out 11 patients with prior VEGF inhibitor therapies achieved a partial response, all 3 patients without prior anti-VEGF treatment had a partial response. In agreement with prior results in prostate cancer, cabozantinib showed meaningful activity in osteoblastic bone lesions supporting the preclinical relevance of MET and VEGF in regulating osteoblast function [92]. Adverse events profile was consistent with prior studies with cabozantinib and included grade 3 diarrhea (20%), hypertension (13%), decreased appetite (13%), and fatigue (7%).…”

A Phase I Study of Cabozantinib (XL184) in Patients with Differentiated Thyroid Cancer

“…Both the MET and VEGF signaling pathways appear to be important for regulating the function of osteoblasts and osteoclasts, which are two key cell types in the bone microenvironment that are involved in the development of metastatic bone lesions (28). In nonclinical studies, cabozantinib blocked progression of both osteoblastic and osteolytic lesions in prostate cancer xenografts in bone (29)(30)(31). In this study, activity of cabozantinib on existing bone lesions was observed.…”