Abstract LB-375: Development of new compounds specifically targeting prostate cancer bone metastases

Abstract

Abstract Introduction: Bone metastases are a major cause of morbidity for men with prostate cancer (PCa). Although PCa cells produce osteoblastic metastases, there is an initial and ongoing osteoclast (OC)-mediated osteolytic phase that is essential for PCa bone metastases. OC-mediated bone resorption is dependent upon OC secretion of bone acid phosphatase. PCa cells in bone secrete high levels of prostatic acid phosphatase (PAP) which differs from BAP in that PAP enzymatic activity is inhibited by tartrate and glyceric acid, whereas BAP is tartrate-resistant. Hypothesis: PAP secreted by human PCa cells in bone acts similarly to OC-derived bone acid phosphatase to degrade bone matrix and enhance PCa bone-targeting and growth in bone. We developed new compounds consisting of glyceric acid or tartrate (known PAP inhibitors) conjugated to a bisphosphonate to inhibit PCa bone metastases. Methods: PCa bone metastases derived from 7 patients were immunostained for androgen receptor (AR), prostate specific antigen (PSA) and PAP expression. The VCaP human PCa cell line derived from a vertebral metastases was inoculated intratibially into SCID mice (n=8) and bone lesions immunostained for AR, PSA, and PAP. Co-cultures of MC3T3 osteoblasts and VCaP cells were treated with tartrate and the effects on cell number, PAP and bone alkaline phosphatase (ALP) secretion measured by ELISA. Glyceric Acid and Tartaric acid were then conjugated with alendronate and the effects of these new conjugates on PAP enzymatic activity were compared to alendronate alone and tartrate alone. Results: Human PCa bone lesions (7/7) had strongly positive expression of PAP, with little AR or PSA expression. 8/8 SCID mice inoculated with VCaP cells intratibially developed osteoblastic VCaP lesions and these similarly had high PAP expression and no PSA expression. Tartrate addition to co-cultures of VCaP and MC3T3 osteoblasts reduced MC3T3 cell numbers and ALP secretion. In vitro testing of the conjugates revealed that the glyceric acid-alendronate conjugate inhibited PAP enzymatic activity but the tartrate-alendronate conjugate and alendronate alone had no significant inhibitory activity. Discussion: We have evidence that PAP secretion by PCa cells enhances their bone metastatic ability. We have developed new bone-targeting agents that consist of alendronate conjugated to PAP-inhibitory small molecules for further development as oral agents to prevent and treat PCa bone metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-375.