Inhibition Of Mammalian Target Of Rapamycin (Mtor) Signaling By Temsirolimus As A Potential Therapeutic Strategy For Esophageal Cancer Treatment

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL [Introduction] Mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase involved in 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. Recently, chemical inhibitors against mTOR have been synthesized and Temsirolimus, an analog of rapamycin, has been approved for clinical usage to renal cell carcinomas. Since esophageal cancer is one of the most aggressive cancers with poor prognosis, we aimed to explore a potential effectiveness of Temsirolimus as a new therapeutic option to treat esophageal cancer. [Methods] Firstly, we performed immunohistochemistry for phosphorylated mTOR in fifty-eight cases of surgically resected esophageal squamous cell carcinoma (ESCC) tissues and cultured ESCC cell lines (TE-1, TE-8, and TE-10) to compare its expression to normal esophageal epithelial tissues or primary esophageal epithelial cells. Next we treated these ESCC cells with a novel mTOR inhibitor, temsirolimus to determine its inhibitory effects on the expression of the downstream molecules and cancer cell growth. Furthermore, we administered temsirolimus weekly to nude mice with subcutaneous or orthotopic xenograft with TE-8 cells to obtain its antitumor effects and a benefit of prolonged survival. [Results] The expression of phosphorylated mTOR was increased in 46 of 58 ESCC tumors (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I alpha (HIF-1α), one of the downstream effectors of mTOR. Temsirolimus treatment apparently suppressed mTOR phosphorylation and the activation of its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice. [Conclusion] As the increased activity of mTOR signaling can be critical for ESCC progression, our study may contribute to developing an alternative therapeutic strategy for ESCC, by targeting mTOR with Temsirolimus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4415. doi:10.1158/1538-7445.AM2011-4415