Abstract 2851: Cabozantinib (XL184) inhibits prostate tumor growth and bone lesion development

Abstract

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Over 80% of advanced prostate cancers (PCa) metastasize to bone resulting in primarily osteoblastic bone lesions. Cabozantinib (CABO) is a multi-kinase inhibitor that targets MET and vascular endothelial growth factor receptor-2 (VEGFR2). Administration of CABO to men with PCa bone metastases has been shown to induce a marked resolution of lesions on bone scan as well as regression of measurable disease. Modulation of prostate specific antigen (PSA) appeared to be independent of changes in other parameters such as target lesions and bone scan. The current study was designed to determine mechanisms underlying CABO activity in PCa. Expression of MET and VEGFR2 or modulation of their activity were verified in PCa cell lines such as PC-3 or the pre-osteoblast cell line MC3T3-E1. To evaluate if CABO impacts PCa neoplastic phenotypes, PCa cell lines LNCaP, C4-2B and PC-3 were treated. CABO inhibited cell viability, migration and invasive ability and promoted apoptosis in LNCaP, C4-2B and PC-3 cells. To determine if CABO could directly modulate PSA expression, LNCaP (androgen dependent) and C4-2B (androgen independent) cells were incubated in the presence or absence of CABO. CABO increased both PSA and androgen receptor (AR) mRNA and protein expression in the LNCaP cells but did not modulate PSA expression in C4-2B cells. MC3T3-E1 and ST2 cells were treated with CABO to evaluate impact on osteoblastogenesis. CABO decreased cell viability and modulated osteocalcin levels in MC3T3-E1 and ST2 cells. ACE-1 canine osteoblastic PCa cells were injected into the tibia and treatment with CABO was started after tumors had developed to determine the impact on PCa growth in vivo. CABO decreased both ACE-1 tumor burden and tumor-induced osteoblastic activity in bone. In contrast, when PC-3 cells (osteolytic) were injected subcutaneously or into the tibiae of mice, which were treated with CABO or vehicle once tumors were established, CABO slowed the growth of PC-3 tumors in the soft tissue but not in bone. These findings indicate that CABO inhibits prostate tumor growth and tumor-induced bone lesion development through direct targeting of both PCa cells and osteoblasts. These studies provide a strong rationale to further elucidate the effect of CABO on osteoblastogenesis and PSA modulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2851. doi:1538-7445.AM2012-2851