Abstract 1162: Castration-resistant prostate cancer bone metastasis model to assess new therapeutics

Abstract

Abstract The role of androgens in the regulation of growth of primary prostate cancer is well established but less recognized in the context of advanced bone metastatic disease, which is the cause of high morbidity in patients. At advanced stage, prostate cancer cells typically lose their dependence on endogenous androgens leading to metastatic castration resistant prostate cancer (mCRPC). The aim of the study was to establish a novel mCRPC model resembling clinical aspects of the bone metastatic disease, which could be used for the evaluation of efficacy of new therapies. To obtain a model for castration resistant growth, 5-6 weeks old NOD.Scid male mice were divided into three study groups. Mice in two study groups were castrated either before inoculation of the cancer cells or at four weeks after inoculation when the tumors were already growing. The mice in one study group were left intact. All mice received an intratibial injection of 2x106 VCaP human prostate cancer cells originally derived from vertebral metastatic site. Tumor growth was followed biweekly for 16 weeks by PSA measurements and X-ray imaging of tumor induced bone changes (lesions). At endpoint, androgen dependent organs were weighed and tumor-bearing tibias were subjected to histological evaluation. At endpoint, a tumor take of 60%, 40% and 50% was observed in the intact mice and in the mice castrated one week before and four weeks after VCaP cell inoculation, respectively. Tumor take was assessed by PSA, X-ray and histology at endpoint. The PSA levels were higher in the intact mice and in the mice castrated at four weeks compared to the mice castrated before cancer cell inoculation. The PSA levels became detectable between 6-8 weeks after cancer cell inoculation in the intact mice and in the mice castrated at four weeks. In the mice castrated before cancer cell inoculation the PSA levels started to increase very late at 14-16 weeks. VCaP cells induced mainly new bone formation, an osteoblastic bone reaction typical for prostate cancer patients. In castrated mice, fewer bone lesions were observed compared to intact mice. The bone lesion areas quantified from X-ray images were larger in the intact mice compared to the mice castrated before cancer cell inoculation. As expected, the weight of androgen dependent organs was lower in the castrated mice compared to the intact mice. In conclusion, a model mimicking important clinical aspects of castration resistant prostate cancer bone metastases was established. Tumor take and growth rates indicated that early phases of tumor development into the bone are androgen dependent whereas tumor growth at later stage relies on the bone microenvironment. The results highlight the significance of the tumor microenvironment in establishing clinically relevant preclinical models for drug development. Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli, Pascale Lejeune. Castration-resistant prostate cancer bone metastasis model to assess new therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1162.