Preclinical Data Presented at AACR Describe a Mechanism of Action of Cabozantinib in a Prostate Cancer Bone Metastasis Model

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)– Exelixis, Inc. (NAS: EXEL) announced the presentation of preclinical data that provide insight into the mechanism of action of its lead compound, cabozantinib, with respect to its activity against prostate cancer tumors that have metastasized to the bone. Timothy Graham, a researcher at The Institute of Cancer Research in London, UK, presented the data (abstract #3924) today in a poster presentation session at the American Association for Cancer Research (AACR) Annual Meeting 2013, which is being held April 6-10, 2013, in Washington, D.C.

Previously reported clinical findings with cabozantinib in castration-resistant prostate cancer (CRPC) patients with bone metastases have included a 67% rate of bone scan response, reduced ⁹⁹Tc-MDP uptake, and reductions in plasma markers of osteoclast activity. In addition, an increase in tumor apparent diffusion coefficient (ADC) measured using diffusion-weighted MRI was reported in a cabozantinib-treated CRPC patient with a bone scan response. Based on these observations, studies of cabozantinib in preclinical models of prostate cancer bone metastases were undertaken to understand the mechanism(s) of action underlying these effects.

In the poster presented today, the investigators reported on a refined prostate cancer bone metastasis model that develops many of the features associated with bone metastases in CRPC patients. In this model, injection of VCaP prostate cancer cells expressing luciferase (to allow bioluminescent imaging of tumors) into the tibiae of mice induced aberrant bone remodeling and development of tumor bone lesions. Both histological analysis of tissue sections and radiological imaging showed the development of extensive osteosclerosis, with abnormal new bone protruding from the tibiae as well as osteolysis resulting in destruction of normal bone structures. This was accompanied by increased numbers of osteoclasts at the sites of bone remodeling. A large increase in ⁹⁹Tc-methylene diphosphonate (MDP) uptake was observed at the site of the bone lesions as measured by single photon emission computed tomography (SPECT) imaging. ⁹⁹Tc-MDP bone scans are routinely employed in clinical practice to detect bone metastases in CRPC patients.

Treatment of tumor-bearing animals with cabozantinib resulted in rapid and substantial inhibition of tumor growth evident by both bioluminescent and magnetic resonance imaging (MRI) techniques. Monitoring tumors in cabozantinib-treated animals using diffusion-weighted MRI showed a significant increase in the apparent diffusion coefficient (ADC) compared to tumors in vehicle-treated animals. Increases in ADC are the result of increased mobility of water molecules in the tumor, and have been shown to correlate with tumor cell death. Consistent with these findings, histological …read more

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