Systemic and Gene Modified Mesenchymal Stem Cell Therapy for Metastatic Prostate Cancer

摘要

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 produced high-titer recombinant AAV vectors encoding osteoprotegerin, and noggin and currently testing the feasibility of MSC therapy for reducing bone burden initiated by cancer growth. Continuation of the ongoing studies in to next year will provide valuable information on therapeutic effects of this therapy for prostate cancer bone metastasis.