Prostate Cancer Bone Metastases
The laboratory is investigating the mechanism underlying the predilection of prostate cancer to metastasize to bone. 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.
In studies funded by the Department of Defense, we uncovered a role for cyclo-oxygenase-2 (COX-2) and PGE2 in these processes. In addition, we reported that androgens target bone osteoblasts and, via induction of canonical Wnt signaling, enhance the growth of prostate cancer cells in the bone microenvironment.
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 from bone matrix, thereby aiding both bone-targeting and growth in bone of PCa cells. 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).
We have preliminary data demonstrating that PAP is highly expressed in PCa bone metastases and that the inhibition of PAP with tartrate prevents osteoclast differentiation and their in vitro bone-resorbing ability. Based on this preliminary data we are currently testing the effects of small molecule inhibitors of PAP enzymatic activity (tartrate and glyceric acid) on prostate cancer bone metastases in an animal model system. In addition, we have applied for a patent on new drugs which combine either tartrate or glyceric acid with a bone-targeting bisphosphonate, alendronate, for the prevention and treatment of prostate cancer bone metastases.