Abstract #2814: Targeting mTOR by temsirolimus as a potential therapeutic alternate in esophageal cancer

Introduction: Mammalian target of rapamycin (mTOR) is 289-kD serine threonine kinase involvedin the control of translational initiation by activating its downstream molecules such as S6 kinase and 4E-BP1 and therefore plays a critical role for cell proliferation, survival and angiogenesis, each of which is infinitely activated during cancer progression. In preclinical studies, mTOR inhibitor resulted significant antitumor activities in a variety of human cancer models, such as gliomas, sarcomas, prostate cancer, breast cancer, small cell lung cancer, melanoma, and leukemia. Temsirolimus an analogue of rapamycin, is a novel mTOR inhibitor that has been clinically used for renal cell cancer treatment. In this report, we determined a potential effectiveness of temsirolimus as a new therapeutic agent for esophageal cancer, which is well recognized as one of the most aggressive malignancies in the world. Materials and Methods: Upregulation of mTOR in esophageal cancer was assessed by western blot and immunohistrochemistry using four cancer cell lines (TE1, TE8, TE10, and SEG-1) and paraffin sections of esophageal cancer tissues. Cultured esophageal cancer cells were treated with temsirolimus to determine its growth inhibitory effect. Western blot was performed to assess the expression levels of mTOR and its downstream molecules. Cell cycle status was analyzed by flowcytometry. Furthermore, to determine its antitumor effect in vivo, subcutaneous tumors were formed on the back of nude mice and weekly administration of temsirolimus was given to these animals. Results: Compared to normal esophageal epithelial cells and esophageal epithelium, mTOR was obviously overexpressed and activated in esophageal cancer cells as well as esophageal cancer tissues. When cultured esophageal cancer cells were treated with temsirolimus, their growth was strongly suppressed, without an apparent induction of apoptosis. Cell cycle analysis revealed that temsirolimus-treated cells accumulated in G1 phase but not in sub-G1 phase, suggesting that the effect of temsirolimus on cell growth may be silencing rather than cytotoxic. Western blot analysis demonstrated that the treatment with temsirolimus at a concentration of 1nM of temsirolimus treatment appeared to be sufficient for a drastic inhibition of mTOR and S6 activations. Finally, subcutaneous tumor growth was significantly suppressed by a weekly administration of temsirolimus. Conclusion: We demonstrated cytostatic and antitumor effects of temsirolimus in esophageal cancer cells in vivo and in vitro. Targeting mTOR by temsirolimus may be a promising therapeutic alternate in esophageal cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2814.