Abstract PR6: Cabozantinib (XL184) inhibits androgen-sensitive and castration-resistant prostate cancer in the bone and increases bone formation in non-tumored bones

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Abstract Bone metastases are the major cause of morbidity and mortality in advanced PCa, and there is therefore a critical need for novel effective therapies for PCa associated bone metastases. The objective of our studies was to evaluate in detail efficacy and mechanisms of action of cabozantinib in androgen-sensitive and castration-resistant PCa in the bone. Cabozantinib (XL184) is a potent dual inhibitor of MET and VEGF receptor 2 (VEGFR2) as well as other receptor tyrosine kinases (e.g., AXL and KIT) that have been implicated in cancer progression. In the clinical setting, cabozantinib demonstrated encouraging signs of clinical benefit in patients with metastatic castration-resistant PCa. However a detailed investigation of the effects of cabozantinib on PCa and bone in the preclinical setting has not been reported. In our preclinical studies we directly injected PCa cells into mouse tibiae and evaluated effects of cabozantinib on an androgensensitive LuCaP 23.1 xenograft that elicits an osteoblastic reaction in the bone, and a castration-resistant C4-2B PCa xenograft that elicits mixed osteolytic/osteoblastic lesions. Serum PSA was measured to monitor tumor growth and response to the treatment. Effects of tumor and cabozantinib on bone were evaluated using micro-CT. Cabozantinib inhibited growth of both LuCaP 23.1 and C4-2B in the bone as demonstrated by serum PSA levels (LuCaP 23.1: control: 20.1 ± 0.8ng/ml vs. cabozantinib: 1.5 ±0.4ng/ml, P=0.020; C4-2B: control: 25.0 ± 6.8 ng/ml vs. cabozantinib: 5.8 ± 1.3ng/ml, P=0.0096). Micro-CT analysis showed that cabozantinib treatment resulted in decreased bone formation caused by LuCaP 23.1 (BV/TV: 49% of control, P=0.0056) while increases were detected in C4-2B tumored tibiae (BV/TV: 158% of control; P=0.077). Micro-CT analysis showed that cabozantinib treatment also affected normal bone. BV/TV in non-tumored tibiae of intact mice treated with cabozantinib was 186% of BV/TV of nontumored tibiae from untreated mice (P=0.030). Increases in BV/TV were also detected in castrated mice treated with cabozantinib (136% of control, P=0.0009.) In summary, our preclinical results show that cabozantinib exhibits inhibitory effects on androgen-sensitive as well as castration-resistant tumor cells in the bone environment and suggest that the overall effects of cabozantinib on bone depend on the underlying bone response to the tumor. 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 skeletalrelated events. This abstract is also presented as Poster A20. Citation Format: Holly M. Nguyen, Lisha G. Brown, Ted S. Gross, Douglas A. Laird, Robert L. Vessella, Eva Corey. Cabozantinib (XL184) inhibits androgen-sensitive and castrationresistant prostate cancer in the bone and increases bone formation in nontumored bones [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr PR6.