title: Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis.
abstract: Bone metastases cause severe skeletal complications and are associated with osteoclast-mediated bone destruction. RANKL is essential for osteoclast formation, function, and survival, and is the primary effector of tumor-induced osteoclastogenesis and osteolysis. RANKL inhibition by its soluble decoy receptor osteoprotegerin (OPG) prevents tumor-induced osteolysis and decreases skeletal tumor burden. Because osteoclast-mediated bone resorption releases growth factors from the bone matrix, the host bone microenvironment induces a vicious cycle of bone destruction and tumor proliferation and survival. A prediction of this vicious cycle hypothesis is that targeting the host bone microenvironment by osteoclast inhibition would reduce tumor growth and survival and may enhance the anti-tumor effects of targeted therapies. The epidermal growth factor receptor (EGFR) pathway regulates critical processes such as cell growth and survival, and anti-EGFR therapies can cause tumor cell arrest and apoptosis. We evaluated whether reduction of osteolysis by RANKL inhibition could enhance the anti-tumor effects of an anti-EGFR antibody (panitumumab) in a novel murine model of human A431 epidermoid carcinoma bone metastasis. Skeletal tumor progression was assessed longitudinally by bioluminescence imaging. RANKL inhibition by OPG-Fc treatment resulted in a reduction in tumor progression in bony sites. OPG-Fc treatment also caused a dose-dependent reduction in tumor-induced osteolysis, supporting the essential role of RANKL in this process. In combination, RANKL inhibition increased the anti-tumor efficacy of an anti-EGFR antibody, and completely blocked tumor-induced bone breakdown, demonstrating that addition of the indirect anti-tumor effect of RANKL inhibition increases the anti-tumor efficacy of panitumumab, a targeted anti-EGFR antibody.
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, CA, USA. jcanon@amgen.com
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bryant
authors.forename: Martine
authors.initials: M
authors.lastname: Roudier
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.forename: Jon
authors.initials: J
authors.lastname: Jones
authors.forename: Robert
authors.initials: R
authors.lastname: Miller
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin / Q000494:pharmacology; D000077544:Panitumumab; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D011897:Random Allocation
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053244:Osteoprotegerin; D053245:RANK Ligand; D000077544:Panitumumab; C541485:EGFR protein, mouse; D066246:ErbB Receptors