Metastatic involvement of the skeleton is a frequent consequence of advanced
prostate cancer. These skeletal
metastases cause a number of debilitating complications and are refractory to current treatments. New therapeutic options are being explored, including conditionally replicating adenoviruses (CRAds). CRAds are engineered to selectively replicate in and destroy
tumor cells and can be 'armed' with exogenous transgenes for enhanced potency. We hypothesized that a CRAd armed with
osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, would inhibit the progression of
prostate cancer bone
metastases by directly lysing
tumor cells and by reducing osteoclast activity. Although
prostate cancer bone
metastases are predominantly osteoblastic in nature, increased osteoclast activity is critical for the growth of these lesions. Ad5-Δ24-sOPG-Fc-RGD is a CRAd that carries a fusion of the
ligand-binding domains of OPG and the Fc region of human
IgG1 in place of the viral E3B genes. To circumvent low
tumor cell expression of the native adenoviral receptor, an
arginine-glycine-aspartic acid (
RGD) peptide insertion within the viral fiber knob allows
infection of cells expressing α(v)
integrins. A 24-base pair deletion (Δ24) within viral E1A limits replication to cells with aberrant
retinoblastoma cell cycle regulator/
tumor suppressor expression. We have confirmed that Ad5-Δ24-sOPG-Fc-RGD replicates within and destroys
prostate cancer cells and, in both murine and human coculture models, that
infection of
prostate cancer cells inhibits osteoclastogenesis in vitro. In a murine model, progression of advanced
prostate cancer bone
metastases was inhibited by treatment with Ad5-Δ24-sOPG-Fc-RGD but not by an unarmed control CRAd.