Exelixis, Inc. Shows Mechanism of Action of Cabozantinib in a Prostate Cancer Bone Metastasis Model

Timothy Graham, a researcher at The Institute of Cancer Research in London, UK, presented the data 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 examination of tumors from cabozantinib-treated animals showed substantial tumor cell death, further validating the link between increases in tumor ADC and anti-tumor activity.

Cabozantinib treatment also resulted in a rapid and sustained reduction of 99Tc-MDP uptake at the site of bone metastasis. Furthermore, radiological imaging showed a normalization of bone architecture, with a significant reduction in sclerotic bone growth and increased trabecular bone growth. Histological analysis showed that this was accompanied by a greatly decreased number of tibial osteoclasts. These preclinical data provide support for the use of 99Tc-MDP bone scan and diffusion weighted MRI as methods for monitoring treatment response to cabozantinib in the clinic.

“In this preclinical study, we investigated cabozantinib’s activity in an animal model of prostate cancer bone metastasis with many of the same features associated with bone metastases in CRPC patients,” said Dr. Simon Robinson, Team Leader for Pre-Clinical Imaging within the Division of Radiotherapy and Imaging at The Institute of Cancer Research in London, UK, and the senior author of the study. “Treatment with cabozantinib resulted in tumor cell death, increases in ADC, and normalization of bone architecture, which was accompanied by reduced uptake of 99Tc-MDP. These results suggest the compound’s effect upon bone metastases is significant and comprised of multiple mechanisms.”

“These preclinical data provide important new insights into the potential impact of cabozantinib on tumors that have metastasized to the bone, and on pathological bone remodeling,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “We are encouraged that these preclinical results highlight the direct anti-tumor activity of cabozantinib against tumors metastatic to bone. We look forward to further characterizing cabozantinib’s activity through our development program in prostate cancer and other tumor types in which bone metastases are prevalent.”