The RANK/RANKL/OPG axis in bone metastasis

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY34-4 One of the most frequent complications of cancer is bone metastasis, which occurs in the majority of patients with advanced breast and prostate cancer and in a significant number of patients with cancers of the kidney, lung, thyroid, or bladder. The sequelae resulting from bone metastases are profound and include severe pain, pathologic fractures, spinal cord compression, hypercalcemia, and other nerve-compression syndromes. Over 100 years ago, Stephen Paget proposed the “seed and soil” hypothesis to explain how the tumor (“seed”) and the metastatic site (“soil”) interact and promote the cancer’s ability to grow and thrive. The interaction of the bone microenvironment and tumor may explain the organ-specific pattern of prostate and breast cancer metastases to the bone. Manipulating the environment of cancer cells in the bone may therefore provide a novel therapeutic approach for the treatment of skeletal tumors. The process of bone remodeling is balanced by the action of two cells: 1) the osteoclasts which resorb bone; and 2) the osteoblasts which deposit bone. Bone metastases have been classified as either osteoblastic or osteolytic; however, this characterization actually represents two extremes of a continuum in which dysregulation of the normal bone remodeling process occurs. In the case of osteoblastic metastases, factors such as endothelin-1, insulin growth factors (IGFs), and transforming growth factor-beta (TGF-beta) may act to increase osteoblast function, resulting in increased bone formation. Importantly, markers of bone resorption are also increased in metastatic prostate cancer, suggesting that osteoclastic activity is also increased in “osteoblastic” lesions. In osteolytic metastatic lesions, the focal lesions are due to the indirect action of tumor cells, which co-opt the physiological mechanisms that normally control bone remodeling. Tumor cells release a variety of factors such as hormones (PTHrP), eicosanoids, growth factors (TGF-alpha, M-CSF), or cytokines (IL-1, IL-6, IL-8, TNF-alpha) which act on bone marrow stromal cells to enhance the production of osteoclast-activating factors including Receptor Activator of NF kappa B-Ligand (RANKL). RANKL is considered the final common mediator of osteoclast activity. RANKL is a member of the TNF superfamily and an essential factor in osteoclast differentiation, survival, and activation. The action of RANKL requires signaling through its cognate receptor, the TNFR family member RANK. Mice containing homozygous deletions of either RANK or RANKL exhibit profound osteopetrosis and a complete lack of osteoclasts, indicating that RANK and RANKL are essential and non-redundant signals that regulate bone resorption. Osteoprotegerin (OPG), another TNFR family member, is a soluble decoy receptor for RANKL and thereby functions as a physiological inhibitor of bone resorption. Alterations of the RANKL/OPG ratio are critical in the pathogenesis of bone diseases that result from excessive bone resorption, including bone metastasis. Although many other cytokines have been shown to influence bone resorption, the primary in vivo effect of these cytokines appears to be indirect, by either increasing RANKL expression or decreasing OPG expression within the bone stroma. Evidence will be presented that the major cytokines and calciotropic factors that operate in cancer-induced bone resorption (eg, PTHrP, IL-1, TNF-alpha) cannot increase osteoclastogenesis and subsequent bone resorption independently of a RANK or RANKL signal. RANKL blockade has been tested in animal models of tumor-induced bone disease using recombinant forms of OPG or a soluble construct of the RANK extracellular domain fused to the immunoglobulin Fc (RANK:Fc). These reagents have been shown to inhibit osteolysis and prevent the progression of skeletal tumor burden in models of hypercalcemia of malignancy and osteolytic bone metastases. In other preclinical studies, RANKL blockade (using RANK:Fc) has also effectively reduced prostate cancer-induced osteoblastic lesions and decreased the prostate tumor burden in the skeleton. A fully human monoclonal antibody to RANKL (AMG 162) has been developed and is being tested in a number of human bone diseases characterized by increased bone resorption. AMG 162 has been evaluated in early clinical trials in various patient populations, including women with breast cancer-related bone metastases, patients with multiple myeloma, and post-menopausal women. The bone antiresorptive activity, safety, and tolerability of AMG 162 in the oncology patients will be presented.