title: Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion.
abstract: 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.
authors.affiliation: New England Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06030-5456, USA.
authors.forename: Mandeep S
authors.initials: MS
authors.lastname: Virk
authors.forename: Farhang
authors.initials: F
authors.lastname: Alaee
authors.forename: Frank A
authors.initials: FA
authors.lastname: Petrigliano
authors.forename: Osamu
authors.initials: O
authors.lastname: Sugiyama
authors.forename: Arion F
authors.initials: AF
authors.lastname: Chatziioannou
authors.forename: David
authors.initials: D
authors.lastname: Stout
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.forename: Jay R
authors.initials: JR
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001859:Bone Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D001862:Bone Resorption / Q000150:complications / Q000473:pathology; D045744:Cell Line, Tumor; D019788:Fluorodeoxyglucose F18; D006614:Hindlimb / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D019485:Bone Morphogenetic Proteins; D053245:RANK Ligand; C517736:Rank-Fc; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins; D019788:Fluorodeoxyglucose F18