RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis

Abstract

Tumor cells induce excessive osteoclastogenesis, mediating pathologic bone resorption and subsequent release of growth factors and calcium from bone matrix, resulting in a ''vicious cycle'' of bone breakdown and tumor proliferation. RANK ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. In metastatic prostate cancer models, RANKL inhibition directly prevents osteolysis via blockade of osteoclastogenesis and indirectly reduces progression of skeletal tumor burden by reducing local growth factor and calcium concentrations. Docetaxel, a well-established chemotherapy for metastatic hormone-refractory prostate cancer, arrests the cell cycle and induces apoptosis of tumor cells. Suppression of osteoclastogenesis through RANKL inhibition may enhance the effects of docetaxel on skeletal tumors. We evaluated the combination of the RANKL inhibitor osteoprotegerin-Fc (OPG-Fc) with docetaxel in a murine model of prostate cancer bone metastasis. Tumor progression, tumor area, and tumor proliferation and apoptosis were assessed. OPG-Fc alone reduced bone resorption (P < 0.001 versus PBS), inhibited progression of established osteolytic lesions, and reduced tumor area (P < 0.0001 versus PBS). Docetaxel alone reduced tumor burden (P < 0.0001 versus PBS) and delayed the development of osteolytic lesions. OPG-Fc in combination with docetaxel suppressed skeletal tumor burden (P = 0.0005) and increased median survival time by 16.7% (P = 0.0385) compared with docetaxel alone.RANKL inhibition may enhance docetaxel effects by increasing tumor cell apoptosis as evident by increased active caspase-3. These studies show that inhibition of RANKL provides an additive benefit to docetaxel treatment in a murine model of prostate cancer bone metastasis and supports clinical evaluation of this treatment option in patients. [Mol Cancer Ther 2008;7(7):2160 -9]

Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells

“…There has been increasing attention assigned to the role of RANKL in regulating cell motility (Jones et al, 2006;Mori et al, 2007;Armstrong et al, 2008;Chen et al, 2010;Hsu et al, 2010;Sabbota et al, 2010) and metastasis (Jones et al, 2006;Miller et al, 2008;Canon et al, 2008;Tan et al, 2011), with a significant emphasis on prostate and breast cancer cell metastasis to bone. Nonetheless, the role of RANK signaling through a homotypic scenario in the context of normal cell motility has yet to be investigated.…”

Erratum: Arming a replicating adenovirus with osteoprotegerin reduces the tumor burden in a murine model of osteolytic bone metastases of breast cancer

“…12,[42][43][44][45] Models employing OPG as a treatment for established bone metastases have also been described, and while OPG has been shown to reduce skeletal tumor burden in this setting, complete elimination of bone metastases from treatment with OPG alone has not been reported. [44][45][46][47] This reflects the difficulty of treating such well-established tumors and is not surprising, given that the ability of OPG to reduce tumor burden in the bone is the product of its antiresorptive activity rather than direct cytotoxicity. 46 We suggest that the delivery of sOPG-Fc by a CRAd has the potential to augment the therapeutic efficacy due to the directly oncolytic effect of viral replication.…”

Role of denosumab in prostate cancer

“…When they used direct histological analysis of the skeletal tumor burden, they found that OPG-Fc and docetaxel reduced histologic tumor burden within the bone by 82% and 83%, respectively. 35 Combination of the treatments enhanced the antitumor effect to 97.5% reduction compared with the control group, upon histological analysis. Median survival time with either OPG-Fc or docetaxel monotherapy did not differ significantly, although the distribution of their effects did.…”

“…26 The tumors cells in bone-treated with 3.0 mg kg --1 OPG-Fc twice weekly demonstrated significantly higher rates of apoptosis compared with control treatment. 26 Miller et al 35 evaluated the therapeutic use of OPG-Fc compared with docetaxel, an antimitotic agent that prevents microtubule depolymerization. Male athymic nu/nu mice were challenged with PC3 prostate cancer cells, and then treated with docetaxel, OPG-Fc, or a combination treatment with both agents.…”

“…Docetaxel was able to reduce both intrabone and extramedullary tumor growth because its effects were independent of tumor localization, whereas OPG-Fc effects are limited to skeletal sites. 26,35 ROLE IN METASTASIS In a study of the effect of direct RANK ligand inhibition in mice with carcinogen-induced mammary tumors, RANK-Fc initiated concurrently with carcinogen administration almost completely inhibited growth of palpable mammary tumors in wild-type mice, an effect not observed with the bisphosphonate (BP) ZA. 33 Moreover, this study also found that RANK-Fc treatment initiated at 5 months in MMTV-neu mice had no significant impact on median time to spontaneous mammary tumor onset, but that it did significantly reduce the total number of mammary tumors quantified at necropsy.…”