Combined therapy with the RANKL inhibitor RANK-Fc and rhApo2L/TRAIL/dulanermin reduces bone lesions and skeletal tumor burden in a model of breast cancer skeletal metastasis

In bone metastases, tumor cells interact with the bone microenvironment to induce osteoclastogenesis, leading to bone destruction and the growth factor release.  RANK ligand (RANKL) is essential for osteoclast formation, function, and survival.  Tumor cell-mediated osteolysis is thought to occur ultimately via induction of RANKL within the bone stroma, and inhibition of RANKL in models of breast cancer bone metastases blocks tumor-induced osteolysis and reduces skeletal tumor burden.  In addition, the skeleton is co-opted by tumor cells and functions as a supportive tumor microenvironment.  Inhibition of RANKL, by reducing tumor-induced osteoclastogenesis, may reduce the local release of growth factors and calcium which may potentially enhance the anti-tumor activity of cytotoxic or direct tumor apoptotic agents.  Recombinant human Apo2 ligand/ TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL/dulanermin) is a dual pro-apoptotic receptor agonist that preferentially induces apoptosis in cancer cells ver...