Prostate cancer is the second most common cancer in men. The major cause of morbidity and mortality in prostate cancer is due to bone metastasis, associated with bone pain, fracture, hypercalcemia, and nerve compression syndromes. In prostate cancer patients with metastatic bone disease, the median survival is approximately 35 months. Histological and electron microscopic analyses have indicated that the bone destruction is mediated both by osteoblasts which form bone, and osteoclasts which resorb bone. Under normal conditions, the rates of bone formation and bone resorption are balanced. However, in prostate cancer patients, the increase in osteoblast number and activity, coupled with an increase in osteoclastic activity adjacent to the osteoblastic lesions, leads to an imbalance in remodeling and to more brittle bone tissue. Despite improvements in the diagnosis and management of prostate cancer, advanced disease with skeletal metastasis remains incurable. Current therapeutic modalities are mostly palliative, and include hormonal therapy, pharmacological management of bone pain, radiotherapy for pain and spinal cord compression, and the use of bisphosphonates to inhibit osteoclast activity. Thus, development of novel targeted therapies to inhibit the onset and progression of bone metastasis in prostate cancer patients will lead to better management of the disease and increase survival.
Recent understanding of the molecular control of osteolytic and osteoblastic signaling has elucidated the role of osteoprotegerin (OPG), a "decoy" receptor that inhibits osteoclastogenesis by binding to RANK ligand, and noggin, a secreted glycoprotein that inhibits osteoblastogenesis through its antagonistic effects on bone morphogenetic proteins (BMP). Thus, potential use of these two molecules by novel approaches can positively impact upon reducing the burden of prostate cancer bone metastasis and increase survival.
To achieve sustained effects of OPG and noggin, gene therapy is more powerful than conventional pharmacological therapies. Since the process of bone metastasis in prostate cancer is a secondary event that occurs in late-stage disease or during recurrence after primary therapy, genetic therapies aimed at controlling this process should be both sustained and localized. Thus, for sustained expression of therapeutic levels of OPG and noggin, vector capable of stable expression of the transgene without vector-associated toxicity and immunity is advantageous. To this end, the adeno-associated virus vector (AAV) is more promising. With recombinant AAV, it is possible to obtain significant therapeutic gains by either systemic or bone-targeted transduction. Some of the salient features of AAV are: (1) AAV establishes a stable persistence in host cells, (2) Long-term expression of transduced genes has been observed in vivo in murine, non-human primate, and human patients, (3) AAV-based vectors are nonpathogenic and less immunogenic, and (4) Recent advances in the technology of recombinant AAV production have resulted in the development of second-generation high-titer vectors without the involvement of a helper virus, overcoming the safety issues concerning clinical-grade vector production. We propose to accomplish therapeutic levels of systemic and bone-targeted OPG and noggin production by using this unique vector system.
Since OPG and noggin act on two different signaling pathways, yet are inter-related in the process of bone remodeling, studying their role in osteoclastic and osteoblastic prostate cancer bone lesions will lead to development of novel therapies. The proposed studies will be evaluated in preclinical mouse models of osteolytic, osteoblastic, and mixed lesions of prostate cancer bone metastasis. We have recently developed a unique approach to enhance genetically modified mesenchymal stem cells to home to bone upon adoptive transfer. The present studies will employ this delivery method and combine a novel real-time noninvasive imaging technology to monitor the effects of OPG and noggin gene therapy in a time-wise manner. Successful outcome of these studies will provide the basis for clinical translation of this approach in future.