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

Cancer Biol Ther. 2010 Apr 1;9(7):539-50. doi: 10.4161/cbt.9.7.11266. Epub 2010 Apr 1.


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 versus normal cells. We therefore examined RANKL inhibition (using RANK-Fc) in combination with rhApo2L/TRAIL on tumor-induced osteolysis and skeletal tumor burden in a murine intracardiac injection model of MDA-MB-231 breast carcinoma bone metastasis. rhApo2L/TRAIL treatment resulted in a rapid reduction of skeletal tumor burden. Treatment with RANK-Fc prevented osteolytic lesions and reduced skeletal tumor burden. Combining RANK-Fc with rhApo2L/TRAIL was superior to either rhApo2L/TRAIL or RANK-Fc alone at reducing skeletal tumor burden in the bone metastasis model. Our findings show that RANKL inhibition effectively inhibits pathologic osteolysis induced by human breast adenocarcinoma MDA-MB-231 cells in animals with established tumors, and also enhances the ability of rhApo2L/TRAIL to reduce skeletal tumor burden in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / secondary
  • Adenocarcinoma / therapy*
  • Animals
  • Apoptosis
  • Blotting, Western
  • Bone Neoplasms / genetics
  • Bone Neoplasms / secondary
  • Bone Neoplasms / therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Therapy*
  • Humans
  • Mice
  • Mice, SCID
  • Osteolysis
  • RANK Ligand / antagonists & inhibitors*
  • Recombinant Fusion Proteins / therapeutic use*
  • Recombinant Proteins / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Tumor Burden


  • RANK Ligand
  • Rank-Fc
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand