This suggests a real challenge for targeted therapy of GBM where very few drugs can reach effective intra-tumor concentrations. Despite the difficulties of developing drugs for direct delivery either by polymer wafer or convention enhanced delivery. Our results are consistent with previous evidence that EGFR inhibition might be beneficial in a subset of patients, but we favor a combination approach based on our in vitro results. This conclusion is based on the fact that only combined inhibition was best at inhibiting signaling in all key pathways. Clinical trials with EGFR inhibitors in GBM have had only modest benefit at best even when accounting for EGFR pathway biomarkers. Recently mathematical modeling of EGFR inhibition in metastatic colon cancer suggests that the likely number of preexisting resistance mutations make it virtually impossible for a single targeting agent to prevent tumor re-growth. Overall, effort might be better used to identify better combinations. Although our best in vitro combination failed to improve over single agent in vivo, the results are informative. We conclude that a combination could include gefitinib, in particular if can be used at higher doses than used currently in the clinic. A kinase inhibitor targeting PDGFRA and/or FGFR or other frequently activated tyrosine kinases that can reach effective intra-tumor concentrations before dose limiting toxicity is a likely candidate for a combination with an EGFR inhibitor for a potentially more effective therapy. Enhanced delivery systems to intracranial tumors may be 
necessary as part of a successful strategy. Histone acetylation and deacetylation are key events in the regulation of chromatin structure. Histone acetyltransferasescatalyze the addition of acetyl groups to the e-amino terminus of lysine residues within histones. Acetylation results in an open chromatin structure by removing positive charges from histones, thus LY2157299 700874-72-2 inducing protein conformational changes, which allows transcriptional machinery to access the DNA and promote transcriptional activity. Histone deacetylasesoppose this process by promoting a closed chromatin structure, which is transcriptionally repressed. Furthermore, histone acetylation marks can function as docking sites for other proteins to interpret the ‘histone code’; for example, the tripartite motif containing 24was recently described as a ‘reader’ protein, which recognises both unmodified histone H3 at lysine 4 and histone H3 acetylated at lysine 23 on the same histone tail resulting in increased gene expression. In addition, non-histone proteins such as p53, ataxia telangiectasia mutated and androgen receptor can also be acetylated resulting in altered protein activity. Hence, protein acetylation and deacetylation can have significant effects on cell function, and for cells to maintain normal growth and differentiation it is important that these two functions maintain equilibrium. In support of this concept, HDAC inhibitors have been found to have wide ranging cellular effects and clinical activity in leukaemia, with Vorinostatbeing approved for clinical use in this disease. Modulation of histone acetylation clearly has therapeutic potential. Tip60, recently renamed KAT5, is a member of the MYST family of HAT enzymes first identified in 1996. Since then many cellular functions have been found to use this protein. Loss of Tip60 results in impaired DNA repair, as this HAT is activated in response to ionising radiation, causing acetylation of histones and FTY720 inquirer activation of p53 and ATM.