Abstract
BackgroundThe mammalian target of rapamycin inhibitor everolimus is approved as an antitumor agent in advanced estrogen receptor-positive breast cancer. Surrogate bone marker data from clinical trials suggest effects on bone metabolism, but the mode of action of everolimus in bone biology remains unclear. In this study, we assessed potential bone-protective effects of everolimus in the context of osteotropic tumors.MethodsThe effects of everolimus on cancer cell viability in vitro and on tumor growth in vivo were assessed. Everolimus-regulated osteoclastogenesis and osteoblastogenesis were also assessed in vitro before we assessed the bone-protective effect of everolimus in a model where bone loss was induced in ovariectomized (OVX) mice. Finally, the role of everolimus in the progression of osteolytic bone disease was assessed in an intracardiac model of breast cancer bone metastases.ResultsAt low concentrations (1 nM) in vitro, everolimus reduced the viability of human and murine cancer cell lines and impaired the osteoclastogenesis of osteoclast progenitors as assessed by quantitative real-time polymerase chain reaction and counting tartrate-resistant acid phosphatase-positive, multinucleated osteoclasts (p < 0.001). Everolimus had little or no deleterious effect on osteoblastogenesis in vitro, with concentrations of 1 and 10 nM increasing the messenger RNA expression of osteoblast marker genes (p ≤ 0.05) and leaving mineralization in differentiated human mesenchymal stem cells unchanged. Everolimus treatment (1 mg/kg body weight/day) prevented the bone loss observed in OVX mice and concurrently inhibited the metastatic growth of MDA-MB-231 cells by 70% (p < 0.002) while preserving bone mass in an intracardiac model of bone metastasis.ConclusionsThese results underline the antitumor effects of everolimus and highlight its bone-protective efficacy, warranting further research on the potential implications on bone health in populations prone to osteoporosis and bone metastases, such as postmenopausal women with breast cancer.
Highlights
The mammalian target of rapamycin inhibitor everolimus is approved as an antitumor agent in advanced estrogen receptor-positive breast cancer
The ability to overcome endocrine resistance was assessed in the pivotal phase III BOLERO-2 trial, where the mammalian target of rapamycin (mTOR) inhibitor everolimus was assessed in postmenopausal women with estrogen receptor (ER)-positive breast cancer, whose disease progressed despite nonsteroidal aromatase inhibition using exemestane [12]
Increasing everolimus concentrations inhibited the phosphorylation of mTOR in a dose-dependent manner, with 100 nM inducing a significant suppression in all three cell lines investigated (p < 0.01) (Additional file 1: Figure S1)
Summary
The mammalian target of rapamycin inhibitor everolimus is approved as an antitumor agent in advanced estrogen receptor-positive breast cancer. Maintaining bone health is a major clinical challenge in patients with breast cancer. Both the disease itself and most forms of treatment exert negative effects on bone metabolism [1, 2]. The ability to overcome endocrine resistance was assessed in the pivotal phase III BOLERO-2 trial, where the mTOR inhibitor everolimus was assessed in postmenopausal women with estrogen receptor (ER)-positive breast cancer, whose disease progressed despite nonsteroidal aromatase inhibition using exemestane [12]. The rate of metastatic bone disease was lower in the combination group [13]
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