Abstract 71: Meningioma: response to retinoids and radiation therapy.

Abstract Meningioma represents one third of all primary central nervous system neoplasms. Most meningiomas are effectively addressed by surgical resection. However unresectable, partially resected, recurrent and high grade meningiomas are also typically treated with adjuvant or definitive radiation therapy. Retinoids are a class of compounds structurally related to Vitamin A. Retinoic acid (RA), the active derivative of vitamin A and the first diffusible morphogen in vertebrates, has recently been evaluated for its chemotherapeutic and chemopreventive attributes in solid tumors. Additionally, a novel orally bioavailable synthetic retinoid, fenretinide, has been tested with different pharmacokinetics, side effect profile, and mechanism of action than the classic retinoids, all-trans retinoic acid (ATRA) and 13-cis-retinoic acid (13CRA). In this project, we study the effects of retinoic acid agents alone and in combination with ionizing radiation in meningioma cell lines (IOMM-Lee and CH157MN). We demonstrate that ATRA, 13CRA and fenretinide have similar (increasing) toxicity profiles in both cell lines at doses above 1μM; but below this concentration there are minimal changes on cellular proliferation. Pretreatment of meningioma cell lines with ≤1μM doses of ATRA and 13CRA protected cells from radiation-induced cell death, while pre-treatment with fenretinide had no effect. Using flow cytometric analysis, we demonstrated that RA inhibited radiation-induced G2/M phase accumulation. Western blot result showed that ionizing radiation increased Phospho-Chk1 and -Chk2 levels, and decreased the levels of cdc25c, Phospho-cdc25c (Ser126) and Phospho cdc25c(THr68), Pre-treatment with RTRA reversed each of these effects in a dose- and time-dependent manner. These data suggest a role for the classic RAs in radiation protection through modulation of DNA repair through cell cycle checkpoint pathways. Fenretinide, however, works through a different mechanism, and does not result in radiation protection. These divergent roles suggest that fenretinide may escape the concerns of radiation protection of earlier retinoids making it a promising agent for tumor treatment in the periradiotherapy period. Citation Format: Xuan Ren, Hannah Lo, Robert Vanderwaal, Jerry Jaboin. Meningioma: response to retinoids and radiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 71. doi:10.1158/1538-7445.AM2013-71