Systemic and Gene Modified Mesenchymal Stem Cell Therapy for Metastatic Prostate Cancer
Annual rept. 1 May 2008-30 Apr 2009
ALABAMA UNIV IN BIRMINGHAM
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Bone is the frequent metastatic site for human prostate cancer resulting in significant morbidity and mortality in patients with advanced disease. The type of bone defect encountered in prostate cancer bone metastasis is osteoblast lesions resulting in excess bone. However, initiation of osteoclastogenesis is first aided by osteolysis, mediated by osteoclasts. The areas provided as source for osteoblast accumulation later leads to thickening of the bone. In this proposal, we planned to address arresting both the events of osteolysis and osteoblastogeneis by biological inhibitors of these two events. Osteoprotegerin OPG is a decoy receptor that competes with RANK for RANKL, thus, modulating the effects of RANKL. Thus, OPG remains an effective molecule for future therapies for bone metastasis. We sought to achieve sustained effects of OPG combining cell therapy and gene therapy approaches. Similarly, for inhibiting osteoblast activity we chose noggin, capable of arresting osteoblast formation. The aims were to determine therapeutic effects of OPG and noggin expression by rAAV gene therapy in a murine model of prostate cancer bone metastasis. So far, we completed studies with OPG by both intramuscular administration of a vector encoding OPG and by genetically-engineering mesenchymal stem cells MSC to express OPG for cell based therapy. Currently we are determining the role of AGR2, a protein identified to play a vital role in prostate cancer bone metastasis. For inhibiting osteoblast lesions, we have produced a vector encoding noggin and determined its therapeutic effects by intramuscular administration using a prostate cancer cell line known to produce osteoblast lesions. Studies using this vector-transduced MSC therapy did not provide significant therapy. We will identify the limitation and possibly overcoming them with alternate approaches. Additional studies to determine the role of AGR2 in prostate cancer bone metastasis will be performed.
- Medicine and Medical Research