Radiation therapy (RT) is one of the most effective and widely used treatments of both primary and metastatic intracranial tumors. Recent technical advances in RT and multimodality approach to treatment have increased the life span of patients. However, a major concern remains as to radiation's effect on long term neurotoxicity and cognitive impairment. Acute and sub acute effects of RT following whole brain RT appear to be reversible, but we hypothesize that these acute changes provide a platform for alteration of the central nervous system (CNS) microenvironment that is responsible for delayed irreversible neurotoxicity. To improve the quality of life of patients and to improve efficacy of whole brain RT, we require effective and targeted approaches to minimize cognitive dysfunction. In order to understand the acute molecular events involved after RT and to identify potential markers that lead to long-term neurotoxicity and dementia, we performed quantitative mass spectroscopy using the iTRAQ (isobaric tag of relative and absolute quantitation) technique on C57 Bl/6 mouse brain tissue extract 72 hours following whole brain RT versus sham-irradiated controls. We found significant changes up- and down-regulation of critical proteins in multiple canonical pathways to be affected, but interestingly some of the most significant changes were in proteins vital to Huntington and Parkinson's signaling pathways. Additionally, we explored the role of Sirtuin 2 (Sirt2), a Class III histone deacetylase which is abundant in CNS and has been shown to mediate oxidative stress response in animal models of neurodegeneration which produce dementia, within the context of whole brain RT. Our aim was to investigate if Sirt2 might be a potential target to mitigate neurotoxic effects induced by RT. Our proteomic analysis of the brain tissue extracts of Sirt2 genomic knockout mice shows that the absence of Sirt2 affects several metabolic and signaling pathways including Huntington, Parkinson's, as well as mitochondrial-mediated signaling. Several factors were found to be uniquely and differentially expressed in Sirt2 knockout tissues under radiation condition. This study indicates that Sirt2 might be a key player in radio sensitization of the CNS and a potential clinical target for minimizing radiation-induced neurocognitive dysfunction.

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 4354. doi:1538-7445.AM2012-4354