The purpose of this study was to investigate the influence of combined inhibition of
receptor activator of nuclear factor kappa-B ligand (RANKL) and
bone morphogenetic protein (BMP) activity in a mixed lytic/blastic
prostate cancer lesion in bone. Human
prostate cancer cells (C4 2b) were injected into immunocompromised mice using an intratibial injection model to create mixed lytic/blastic lesions.
RANK-Fc, a recombinant RANKL antagonist, was injected subcutaneously three times a week (10mg/kg) to inhibit RANKL and subsequent formation, function and survival of osteoclasts. Inhibition of BMP activity was achieved by transducing
prostate cancer cells ex vivo with a retroviral vector expressing noggin (retronoggin; RN). There were three treatment groups (
RANK-Fc treatment, RN treatment and combined RN and
RANK-Fc treatment) and two control groups (untreated control and empty vector control for the RN treatment group). The progression of bone lesion and
tumor growth was evaluated using plain radiographs, hindlimb
tumor size, (18)F-Fluorodeoxyglucose and (18)F-fluoride micro PET-CT, histology and histomorphometry. Treatment with
RANK-Fc alone inhibited
osteolysis and transformed a mixed lytic/blastic lesion into an osteoblastic phenotype. Treatment with RN alone inhibited the osteoblastic component in a mixed lytic/blastic lesion and resulted in formation of smaller osteolytic bone lesion with smaller soft tissue size. The animals treated with both RN and
RANK-Fc demonstrated delayed development of bone lesions, inhibition of
osteolysis, small soft tissue
tumors and preservation of bone architecture with less
tumor induced new bone formation. This study suggests that combined inhibition of the RANKL and the BMP pathway may be an effective
biologic therapy to inhibit the progression of established mixed lytic/blastic
prostate cancer lesions in bone.