Abstract 3987: CaMKK2 inhibition as a "dual-hit" strategy against ADT-induced osteoporosis and bone-metastatic prostate cancer

Abstract

Abstract Prostate cancer (PCa), the most frequently diagnosed cancer in men, will have an estimated 26,730 deaths in the US during 2017. Predominantly, these deaths will be caused due to metastatic disease. PCa preferentially metastasizes to the bone undermining its structural integrity. PCa cells rely on androgens for survival and proliferation. Consequently, androgen deprivation therapy (ADT) is the first line of defense against advanced-stage PCa. However, ADT contributes to significant decreases in bone mass, predisposing the patient to an increased risk of fractures. Hence, there is a critical need for therapies that protect against bone metastatic disease as well as reverse ADT-induced bone loss in PCa patients. Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a direct target of the androgen receptor (AR) and is highly over-expressed in androgen-dependent and independent forms of PCa. In vitro studies have shown that its inhibition suppresses the growth and migration of PCa cells. We observed that CaMKK2 inhibition suppresses 3-D spheroid formation by the androgen-independent PCa cell line C4-2 but not by the androgen-dependent PC3 cells. However, the exact downstream mechanism by which CaMKK2 regulates PCa growth remains unknown. More recently, CaMKK2 was shown to play a role in both the anabolic and catabolic pathways of bone remodeling. Genetic ablation and pharmacological inhibition of CaMKK2 via STO-609 stimulates osteoblasts and suppresses osteoclasts and confers protection from age- and ovariectomy-induced bone loss in mice. Based on these preliminary data, we hypothesize that inhibition of a single target, CaMKK2, will result in the therapeutic alleviation of two chief complications in advanced-stage PCa, i.e., bone metastatic tumor burden and ADT-induced bone loss. We performed sham or bilateral orchiectomy (ORX) on pretreated (saline/STO-609) 5-week-old male athymic mice (n=15 per cohort). Tri-weekly intraperitoneal (i.p.) injections were continued for 12 weeks. Additionally, two weeks after surgery, sham and ORX mice were intra-tibially injected with C4-2B cells. Micro-computed tomography analyses indicated a prevention of ORX-induced bone loss in STO-609 treated mice compared to saline treated controls (3-fold, p<0.05). Radiographic and histomorphomteric analyses reveal a decrease in C4-2B-initiated bone lesions in STO-609 treated mice compared to the saline treated cohorts. Taken together, our studies represent a highly novel and unique approach in the treatment of advanced-stage PCa. Citation Format: Ushashi Dadwal, Justin Williams, Austin Pucylowski, Eric Chang, Khalid Mohammad, Theresa Guise, Uma Sankar. CaMKK2 inhibition as a "dual-hit" strategy against ADT-induced osteoporosis and bone-metastatic prostate cancer [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 3987.