Abstract #156: Is irinotecan and rapamycin combination, targeting mTOR/HIF-1 alpha axis, a new effective therapy in high grade brain tumors?

Despite new therapeutic managements in high grade gliomas, these brain tumors remain highly resistant with a worse outcome. Then, developing novel therapeutic approaches is a real need to improve the patient survival. Based on the recent developments in our Lab in colon cancer cell lines and xenografted human colon tumors (Pencreach et al., work in press in Clinical Cancer Research), where the combination of irinotecan with mTOR inhibitors was effective through mTOR/HIF-1 alpha axis inhibition, we designed the same preclinical approach to evaluate the efficiency of this new combination in high grade glioma cell line U87. Furthermore, the mTOR/HIF-1 alpha pathway is known to be implicated in several publications about high grade glioma angiogenesis or the role of PTEN loss in glioblastoma. This molecular axis could be as in colon cancer targeted at 2 independent steps. Material and Methods: U87 was chosen to begin the validation of this combination because of its known irinotecan sensitivity. All cell cultures were done in hypoxic conditions. U87 cell lines were treated with low doses of irinotecan alone (1\#956;M), rapamycin alone (20 nM) or combination of both drugs. Cellular effects were further characterized with in vitro cell aspects and protein HIF-1 alpha expressions. Results: Under hypoxic conditions (1% O2), in vitro experiment with the drugs alone, showed a reduction of cell proliferation but, with the combined treatment, a complete inhibition of nanosphere production. The protein analysis of cell lysates also showed a complete inhibition of HIF-1 alpha protein in the therapeutic combination whereas the drugs alone only decreased partially the protein expression. This dramatic effect after exposure to both drugs at low concentrations underlined the potential cytotoxic effect mediated through HIF-1 alpha inhibition in a high grade glioma cell line. Conclusion: These results identify HIF-1 alpha as a promising target and, after further preclinical testing in xenografted mice with U87 cell lines, they would provide a clear rationale to use irinotecan and mTOR inhibitors in combination in human high grade gliomas.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 156.