Abstract 849: Cabozantinib (XL184) inhibits growth of prostate cancer in the bone and results in an altered bone environment
Authors: Nguyen Holly M. , Brown Lisha G. , Gross Ted S. , Vessella Robert L. , Schimmiller Frauke , Corey Eva 
Published: August 2012

Abstract
There is a critical need for novel effective therapies for advanced prostate cancer (PCa) and associated bone metastases. A great deal of focus is being placed on investigations into the use of small molecule kinase inhibitors. Cabozantinib (XL184) is a small molecule kinase inhibitor which potently inhibits MET and VEGF receptor 2 (VEGFR2). In a phase 2 adaptive randomized discontinuation trial cabozantinib has demonstrated encouraging signs of clinical benefit in patients with metastatic castration-resistant PCa. Complete or partial resolution of lesions was evident in 82 of 110 (76%) patients with bone metastases as assessed by bone scan. The objectives of our preclinical studies were to investigate the efficacy of cabozantinib on growth of androgen-sensitive and castration-resistant PCa in the bone and on the bone itself. For our in vivo studies we used the androgen-sensitive LuCaP 23.1 PCa xenograft that elicits an osteoblastic reaction in the bone, and the castration-resistant C4-2B PCa xenograft that elicits mixed osteolytic/osteoblastic lesions. Cabozantinib inhibited growth of LuCaP 23.1 in the bone as demonstrated by serum PSA levels (control: 20.1± 0.8ng/ml vs. cabozantinib: 1.5 ±0.4ng/ml, P=0.020). Micro-CT analysis of trabecular bone showed that LuCaP 23.1 growth in the bone resulted in significant increases in bone volume (BV: 7.6 fold increase vs non-tumored tibiae; P=0.017). These increases were attenuated by cabozantinib (BV: 1.3 fold increase vs non-tumored tibiae, P=0.0021). Micro-CT analysis also showed that cabozantinib treatment affected normal bone. BV in non-tumored tibiae from mice treated with cabozantinib was 1.8 fold higher than BV of non-tumored tibiae from untreated mice (P=0.013). To evaluate the effects on osteoblasts in vitro we used MC3T3 cells. In concordance with the detected effects on normal bone, cabozantinib increased alkaline phosphatase activity in MC3T3 cells (1-3 μM, 1.5-2.2 fold increases, ANOVA P&lt;0.0001) and their mineralization (3 μM: 2.2 fold increase, P=0.0023). In the castration-resistant model, C4-2B, cabozantinib treatment also significantly decreased tumor growth based on serum PSA (control: 24.93±6.80 ng/ml vs. cabozantinib: 5.77±1.29 ng/ml, P=0.0096). Micro-CT assessment of tibiae from the C4-2B study and further analyses of all generated tissues are ongoing to further investigate the mechanisms underlying cabozantinib efficacy.In summary, our preclinical results show that cabozantinib is an effective inhibitor of androgen-sensitive as well as castration-resistant PCa in the bone. Importantly our data also indicate that cabozantinib treatment results in increases in bone formation which might be particularly beneficial to patients with advanced PCa who are on androgen ablation therapy and experiencing decreases in bone mineral density and increased frequency of skeletal-related events.
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 849. doi:1538-7445.AM2012-849