The isoprenoid biosynthetic pathway (IBP) provides substrates for the post-translational modification of key proteins in regulating malignant cell properties, including proliferation, migration, and invasion. Several studies have found broad inhibitors of the IBP, such as statins, to significantly reduce the risk of advanced prostate cancer (PCa), potentially through their induced-reduction of geranylgeranylated proteins. However, such inhibition of the entire IBP is limited by side effects resulting from depletion of all isoprenoids and their products. We have developed a novel compound, geranylgeraniol bisphosphonate (GGOHBP), selectively targeting geranylgeranyl diphosphate synthase (GGDPS) and reducing the post-translational modification of geranylgeranylated proteins. Luciferase-expressing human-derived 22Rv1 PCa cells were injected into the left ventricle of 20 mice using bioluminescence imaging (BLI) to visualize tumor development. After three weeks 18/20 mice had developed tumors and daily subcutaneous (SQ) injections of 1.5mg/kg GGOHBP were given for one month. All 18 mice developed mandible tumors, 13 developed adrenal gland tumors, 4 developed intestinal tumors, 2 developed femoral tumors, 2 developed liver tumors, and 1 developed a tumor in an unidentified location in the chest cavity. Ex vivo photon count analyses revealed an 80% (p=0.1458) reduction in adrenal gland tumors of the treated mice as compared to vehicle-treated controls. This corresponded to a 54% (p=0.0007) reduction in total adrenal gland tumor weight in the treated as compared to the control mice. Western blot analysis of the adrenal gland tumors and one intestinal tumor showed a reduction in Rap1A geranylgeranylation in the treated mice and not the control mice, while non-tumorous tissues showed no Rap1A alteration. A follow-up study of non-tumor bearing mice given SQ injections of 1.25 or 1.5 mg/kg GGOHBP daily did not reveal alterations in Rap1A geranylgeranylation in the adrenal glands, kidneys, liver, or heart. Our findings detail a novel compound capable of preferentially altering the IBP in the adrenal gland tumors of a murine model of metastatic PCa. Future work defining the mechanism behind this focal effect and the adrenal gland isoprenoid environment will allow compound optimization and further understanding of the IBP's role in PCa metastasis.

Citation Format: Jacqueline E. Reilly, Jeffrey D. Neighbors, Nadine Bannick, Michael D. Henry, Craig H. Kuder, Raymond J. Hohl. Targeting the isoprenoid biosynthetic pathway in a murine model of metastatic prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4032. doi:10.1158/1538-7445.AM2014-4032

©2014 American Association for Cancer Research.
2014