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A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing (Neo)adjuvant Therapies
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Inhibition of mTOR radiosensitizes soft tissue sarcoma and tumor vasculature

James D Murphy1, Aaron C Spalding, Yash R Somnay

  • 1Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-5010, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 17, 2009
PubMed
Abstract

Insights

Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), radiosensitizes soft tissue sarcoma by targeting tumor and endothelial cells. This suggests rapamycin combined with radiotherapy warrants clinical trials for soft tissue sarcoma treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Radiation Oncology

Background:

  • The PI3K/Akt/mTOR pathway is often upregulated in soft tissue sarcoma.
  • Mammalian target of rapamycin (mTOR) inhibitors, like rapamycin, show promise in treating soft tissue sarcoma and radiosensitizing other cell types.

Purpose of the Study:

  • To investigate if rapamycin can enhance the effects of radiation therapy (radiosensitize) in soft tissue sarcoma and endothelial cells, both in laboratory settings and in living organisms.
  • To determine if this radiosensitization is achieved through the inhibition of mTOR.

Main Methods:

  • Colony formation assays were used to test rapamycin's radiosensitizing effects on three human soft tissue sarcoma cell lines and human dermal microvascular endothelial cells (HDMEC).
  • Microvascular sprouting assays evaluated the combined effects of rapamycin and radiation on endothelial cells.
  • In vivo studies involved treating SK-LMS-1 soft tissue sarcoma xenografts in nude mice with daily rapamycin and/or radiation for three weeks.

Main Results:

  • Rapamycin demonstrated radiosensitizing effects on all tested soft tissue sarcoma cell lines at low, non-toxic doses.
  • Tumor growth delay was significantly greater in mice treated with both rapamycin and radiation compared to either treatment alone.
  • Rapamycin effectively inhibited mTOR signaling, counteracting radiation-induced increases, and reduced microvessel sprouting in endothelial cells without affecting their colony formation.

Conclusions:

  • Low doses of rapamycin inhibit the mTOR pathway and radiosensitize soft tissue sarcoma in vitro and in vivo.
  • Rapamycin synergizes with radiation to inhibit endothelial microvessel formation, suggesting a dual targeting approach.
  • These findings support the potential of combining rapamycin with radiotherapy for soft tissue sarcoma and warrant clinical trials.

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