Reference - Detail
| RRC ID | 44672 |
|---|---|
| Author | Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, Schimmoller F, Keller ET. |
| Title | Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. |
| Journal | Clin Cancer Res |
| Abstract |
PURPOSE: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. EXPERIMENTAL DESIGN:Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro 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. 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 antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy. |
| Volume | 20(3) |
| Pages | 617-30 |
| Published | 2014-2-1 |
| DOI | 10.1158/1078-0432.CCR-13-0839 |
| PII | 1078-0432.CCR-13-0839 |
| PMID | 24097861 |
| PMC | PMC3946460 |
| MeSH | Anilides / pharmacology* Animals Antineoplastic Agents / pharmacology* Bone Neoplasms / secondary* Cell Line, Tumor Cell Proliferation / drug effects* Disease Models, Animal Humans Immunoblotting Immunohistochemistry Male Mice Mice, SCID Osteoblasts / drug effects* Prostatic Neoplasms / pathology* Pyridines / pharmacology* Xenograft Model Antitumor Assays |
| IF | 10.107 |
| Times Cited | 57 |
| WOS Category | ONCOLOGY |
| Resource | |
| Human and Animal Cells | ST2(RCB0224) |