Abstract 1524: Overcoming temozolomide resistance in MGMT positive glioblastoma by targeting ALDH1

Abstract Despite aggressive therapy, including radical surgical resection, radiation, and chemotherapy, the prognosis for patients with glioblastoma (GBM) remains poor and relapse occurs regularly. Implementation of the chemotherapy drug temozolomide (TMZ), as a standard in adjuvant GBM therapy, significantly increased the overall survival of patients with an epigenetic silenced MGMT promoter (MGMT-). To date, no comparable therapeutic approach for GBM patients with MGMT expression (MGMT+) is applied. Tumor re-growth in MGMT+ and MGMT- GBM corroborates the tumor stem cell (TSC) paradigm, postulating that a therapy-resistant subpopulation of cells harbors the ability to keep the tumor alive and growing. Recently, we presented aldehyde dehydrogenase 1 (ALDH1) as a marker for glioblastoma cells with stem cell capacity. In this study, we demonstrate that ALDH1 overexpression in established and primary MGMT+ GBM cell lines correlates with resistance to TMZ, while concomitant inhibition of ALDH1 by 4-diethylaminobenzaldehyde (DEAB) or tetraethylthiuramdisulfide (DSF) re-sensibilized the cells significantly. Application of TMZ in combination with DEAB strikingly attenuated the stem cell capacity of both MGMT + and MGMT – cells. For further verification of the specific impact of ALDH1 on therapy resistance, shRNA constructs were applied. Moreover, immunohistochemical analysis of ALDH1 expression in specimens of glioblastoma patients revealed a significant correlation between expression of this enzyme and a poor clinical prognosis. All these findings demonstrate that ALDH1 is a marker for brain tumor stem cells, a strong predictor of clinical outcome and a potential target for an improved therapy of MGMT positive GBM. 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 1524. doi:10.1158/1538-7445.AM2011-1524