Osteocalcin-directed gene therapy for prostate-cancer bone metastasis

Osteocalcin (OC) is a major noncollagenous bone protein whose expression is limited almost exclusively to osteotropic tumors and mature calcified tiss ue (differentiated osteoblasts). The function of OC, a highly conserved gam ma -carboxyglutamic acid-containing protein, relies in part on its ability to bind hydroxyapatite and act as a chemoattractant for bone-resorbing cell s. Serum osteocalcin levels are used clinically as an index of active bone turnover. Research in our laboratory has revealed that OC is expressed in s everal solid tumors, including osteosarcoma and ovarian, lung, brain, and p rostate cancers. Evidence arising from reverse-transcription polymerase cha in reaction (RT-PCR; detection of OC mRNA), immunohistochemical staining (d etection of OC protein), and transient transfection and reporter assay (det ection of OC mRNA transcription) reveals that OC expression is up-regulated in numerous solid tumors, with its expression being further elevated in an drogen-independent prostate cancers. A recombinant. replication-defective a denovirus, Ad-OC-TK (OC promoter-driven herpes-simplex-virus thymidine kina se) was constructed and, when combined with the appropriate prodrug, either ganciclovir (GCV) or acyclovir (ACV), was found to be effective at destroy ing prostate-cancer cell lines in vitro and prostate tumor xenografts in vi vo in both subcutaneous and bone sites. Additionally, via use of the OC pro moter the supporting bone stromal cells are cotargeted when the prostate ca ncer interdigitates with bone stroma at the metastatic skeletal sites. Thus , maximal tissue-specific cell toxicity is achieved by the interruption of cellular communication between the prostate cancer and the bone stroma. We describe herein the preclinical foundation as well as the design and implem entation of an ongoing phase I clinical trial at the University of Virginia that targets androgen-independent metastatic prostate cancer using the Ad- OC-TK vector.