ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
Inhibition of mTOR signaling by everolimus has concurrent anti-tumor and bone-protective effects in murine osteolytic cancer models
Andrew Browne 1 , Marie Luise Kubasch 1 , Andy Göbel 1 , Peyman Hadji 2 , David Chen 3 , Martina Rauner 1 , Tilman Rachner 1 & Lorenz Hofbauer 1,
1Technical University Dresden, Dresden, Germany; 2Philipps University of Marburg, Marburg, Germany; 3Novartis Pharmaceutical Corp, New York, USA; 4German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clinical data suggest that the mTOR inhibitor everolimus may have bone protective effects in addition to its anti-tumor effects in women with ER+/HER2− metastatic breast cancer receiving hormone-ablative therapies. Based on these findings, we tested the hypothesis, whether everolimus exerts concurrent anti-tumor effects while protecting the skeleton in murine models. Thus, we assessed bone metabolism and anti-tumor effects in osteolytic cancer models upon exposure to everolimus. In vitro, everolimus concentrations of 1 nM were sufficient to significantly (P<0.01) reduce the viability of various breast cancer cell lines (MCF-7, MDA-231 and MDA-Bone). Moreover, everolimus significantly reduced the number of TRAP- positive cells in both RAW 264.7 cells and murine derived osteoclasts at concentrations of ≥10 nM, indicating a potent anti-osteoclast effect. Consistently, the expression of markers of osteoclast activity, including TRAP and cathepsin K was also decreased. Furthermore, reduced viability and function was observed in human-derived mesenchymal stem cells (hMSC) only when exposed to higher concentrations (≥100 nM) of everolimus. When immunocompetent C57BL/6 mice were inoculated subcutaneously with osteotropic, murine B16-F10 melanoma cells and exposed to everolimus at a low dose of 1 mg/kg per day for 2 weeks, tumor growth was inhibited (P<0.01). This was confirmed in a subcutaneous MDA-MB-231/immuno-compromised BALB/c breast cancer mouse model. In ovariectomized C57BL/6 mice, a dose of 1 mg/kg per day for 4 weeks significantly mitigated the suppressive effect of hormone deprivation on femoral bone mass assessed by μCT (P<0.05). In summary, our data indicate that low concentrations of everolimus are capable of concurrently inhibiting tumor growth while preserving bone mass in vivo. These results warrant further research on the potential bone protective effects of everolimus in a population exposed to a high risk of osteoporosis and bone metastases, such as women with breast cancer.
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Bone Abstracts
ISSN 2052-1219 (online)
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