Inhibition of mTOR radiosensitizes soft tissue sarcoma and tumor vasculature.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Murphy
James D
JD
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-5010, USA.
Spalding
Aaron C
AC
Somnay
Yash R
YR
Markwart
Sonja
S
Ray
Michael E
ME
Hamstra
Daniel A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D008954:Models, Biological; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D012509:Sarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus