RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases.
BACKGROUND
Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression.


METHODS
We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses.


RESULTS
OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts.


CONCLUSIONS
These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.
*Department of Hematology/Oncology Research, Amgen Inc., Seattle, Washington; and †Therapeutic Innovation Unit, Amgen Inc., Seattle, Washington.
Robert E
RE
Miller
Jon C
JC
Jones
Mark
M
Tometsko
Michelle L
ML
Blake
William C
WC
Dougall
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017984:Enoxaparin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D010014:Osteolysis / Q000188:drug therapy*; D053244:Osteoprotegerin / Q000276:immunology / Q000378:metabolism*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D017984:Enoxaparin; D053244:Osteoprotegerin; D053245:RANK Ligand