Abstract
The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, have recently shown clinical benefit in soft tissue sarcoma, and mTOR inhibition has also been associated with radiosensitization of carcinoma and endothelial cells. This study tested the hypothesis that rapamycin radiosensitizes soft tissue sarcoma and endothelial cells in vitro and in vivo through the inhibition of mTOR. Colony formation assays were done to determine the radiosensitizing properties of rapamycin on three human soft tissue sarcoma cell lines (SK-LMS-1, SW-872, and HT-1080) and human dermal microvascular endothelial cells (HDMEC). The functional effects of rapamycin and radiation on the endothelial compartment were evaluated with microvascular sprouting assays. The in vivo radiosensitizing activity of rapamycin was assessed with s.c. SK-LMS-1 nude mice xenografts treated with concurrent daily rapamycin, radiation, or both for three weeks. In vitro radiosensitization was shown in all three soft tissue sarcoma cell lines with minimally cytotoxic doses of rapamycin. SK-LMS-1 xenografts displayed significant tumor growth delay with rapamycin and radiation compared with either treatment alone. Radiation resulted in transient increased mTOR function, whereas rapamycin abolished this signaling in irradiated and unirradiated samples. In HDMEC, rapamycin and radiation reduced microvessel sprouting, but did not alter colony formation. Minimally cytotoxic concentrations of rapamycin inhibited the mTOR cascade in culture and in vivo while radiosensitizing soft tissue sarcoma, and produced synergistic effects with radiation on HDMEC microvessel formation. By targeting both tumor and endothelial compartments, rapamycin produced potent radiosensitization of soft tissue sarcoma xenografts. Clinical trials combining rapamycin and radiotherapy in soft tissue sarcoma are warranted.
Highlights
The phosphatidylinositol 3kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) prosurvival pathway is frequently up-regulated in soft tissue sarcoma
In addition to basal activity in oncogenesis, the prosurvival PI3K/Akt/mTOR pathway can be activated in response to radiotherapy [25, 26], which led to preclinical studies combining mTOR inhibitors with radiotherapy
In vivo this combination therapy resulted in greater than additive inhibition of tumor vascular growth and tumor growth delay. These results suggest that combined mTOR inhibition with radiation may provide a unique opportunity to increase tumor control in soft tissue sarcomas
Summary
The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma. In addition to basal activity in oncogenesis, the prosurvival PI3K/Akt/mTOR pathway can be activated in response to radiotherapy [25, 26], which led to preclinical studies combining mTOR inhibitors with radiotherapy These studies showed in vitro radiosensitization in prostate and breast cancer cell lines, and in vivo radiosensitization in prostate, breast, and glioblastoma tumor models [21, 25, 27, 28]. We show that clinically achievable concentrations of rapamycin sensitize both soft tissue sarcoma cells and tumor vasculature to the effects of ionizing radiation In vivo this combination therapy resulted in greater than additive inhibition of tumor vascular growth and tumor growth delay. These results suggest that combined mTOR inhibition with radiation may provide a unique opportunity to increase tumor control in soft tissue sarcomas
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