Abstract
Abstract Recent therapeutic advances have improved control of glioblastomas, with a significant fraction of tumors responding to initial therapies. Unfortunately, all glioblastomas recur and lead to patient death. In an effort to better understand therapeutic resistance, we have explored high-dimensional profiling studies to understand mechanisms of therapeutic resistance and to identify novel therapeutic targets. Temozolomide (TMZ) is an alkylating chemotherapeutic agent that is used to treat all glioblastomas. Recurrent glioblastomas, however, become resistant to the effects of TMZ through a mechanism associated with inactivation of MSH6, a member of the mismatch repair gene family; MSH6-deficient glioblastomas grow more rapidly during TMZ therapy. To explore pathways of therapeutic resistance, we have designed an unbiased drug resistance selection screen to create TMZ-resistant human glioblastoma cell lines using combinatorial zinc-finger transcription factors (ZTFs). The combinatorial ZTF library enables activation of a gene or a set of genes that will be selected for resistance to TMZ. We have isolated resistant clones in the TMZ-sensitive A172 and Gli36 cell lines and present molecular profile analysis of these clones. By comparative gene expression profile analysis of novel ZTF-induced TMZ resistant glioblastoma cell lines, we expect to identify molecular pathways that confer TMZ resistance. In doing so, we also aim to identify possible biomarkers for TMZ resistance in recurrent glioblastomas. 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 1718. doi:10.1158/1538-7445.AM2011-1718
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