Grant title:
Development of New Compounds to Treat Prostate Cancer Bone Metastases

Funding Agency:
Prostate Action, Inc.

Prostate cancer (PCa) preferentially metastasizes to bone with a resulting mortality of  70%. The metastases are associated with crippling complications including severe pain, fractures, spinal cord compression and bone marrow suppression. Unfortunately, there are currently no effective therapies for the prevention or treatment of PCa-induced bone metastases. Although PCa cells are somewhat unique among the solid tumors in that they often produce osteoblastic lesions in bone, accumulating evidence suggests that there is an initial and ongoing osteolytic phase that is essential for both bone targeting and continued growth. PCa cells produce soluble factors that activate osteoclastic bone resorption that, in turn, release growth factors to facilitates their entry into the bone microenvironment. One of the soluble factors produced by PCa cells, particularly from bone metastases, is prostatic acid phosphatase (PAP), the first human serum tumor marker ever described. A different form of acid phosphatase, bone acid phosphatase (BAP), is secreted by osteoclasts for pyrophosphate removal, a step necessary for hydroxyapatite dissolution. PAP and BAP are similar in terms of their overall activity and pH optimum, but the two enzymes can be distinguished by their sensitivity to inhibition by tartate. Namely, while PAP is inhibited by tartrate, BAP is resistant (hence, its name tartrate-resistant acid phosphatase).

This proposal stems from our findings that PAP, actively secreted by human PCa bone metastases, promotes osteoblast differentiation. More importantly, our preliminary data indicate that secretory PAP from human PCa cells activates the differentiation and bone-resorptive ability of osteoclasts in vitro. The question we ask is whether the inhibition of PAP by novel therapeutic agents can prevent and/or treat PCa bone metastases. In response to our question, we hypothesize that PAP secretion by PCa cells plays a pivotal role in their targeting and growth in bone, and that the inhibition of PAP activity may therefore be a novel molecular approach to the treatment of PCa bone metastases. We will inhibitthe enzymatic activity of PAP in a mouse model of human PCa either with tartrate itself or new conjugates that we have developed that combine small-molecule inhibitors of PAP (tartrate and glyceric acid) with the FDA-approved bisphosphonate, alendronate