Abstract 1288: GLI2 is a significant determinant of HH-GLI pathway activaton in Ewing sarcoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Ewing Sarcoma is an aggressive bone and soft tissue malignancy of children, adolescents and young adults. Non-canonical activation of the Hedgehog-GLI pathway by the Ewing specifc EWS/FLI1 transcription factor has been shown to mediate important aspects of tumor phenotype. While evidence regarding the role of EWS/FLI1 in direct activation has been published, no one has yet investigated the role of other pathway components in Ewing tumors. Physiologically, GLI2 is the principal transcriptional activator of GLI1 and substantial amounts of GLI2 can be demonstrated in Ewing tumors and cell lines. So we hypothesized that GLI2 may also function in Ewing cells to help to regulate GLI1 and Hedgehog-GLI pathway activaton. Since GLI2 can be targeted by pharmacologic means, understanding its role in Ewing tumors is of potential significance. We demonstrate that GLI2 is expressed at significant levels in Ewing tumors. Furthermore, we show by overexpression studies, that GLI2 overexpression augments expression of both GLI1 and other pathway targets in Ewing cell lines. By using shRNA, we also demonstrate that knockdown of GLI2 expression has the expected effect of diminishing GLI 1 expression in Ewing lines. Finally, we show that treatment with GLI inhibitors also diminishes GLI2 activation of GLI1. Overall, these data indicate that GLI2 in Ewing cells exists in an activator state in Ewing cells and that pharmacologic means of targeting GLI2 may be an effective strategy for targeted therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1288. doi:1538-7445.AM2012-1288