Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma

Abstract

These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.

Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma

“…Chromatin condensation, moreover, impairs recruitment of DNA repair factors and results in accumulation of DNA breaks. In the past several years, HDAC inhibitors have been used as radio‐ and chemo‐sensitizers in GBM (Lucio‐Eterovic et al., 2008; Singh et al., 2015, 2011; Xu et al., 2011). They induce differentiation, growth arrest and apoptosis in numerous malignant cells in vitro and in vivo (Eyupoglu et al., 2005; Komatsu et al., 2006; Min et al., 2015; Singh et al., 2015, 2011; Xu et al., 2011; Yin et al., 2007).…”

“…In the past several years, HDAC inhibitors have been used as radio‐ and chemo‐sensitizers in GBM (Lucio‐Eterovic et al., 2008; Singh et al., 2015, 2011; Xu et al., 2011). They induce differentiation, growth arrest and apoptosis in numerous malignant cells in vitro and in vivo (Eyupoglu et al., 2005; Komatsu et al., 2006; Min et al., 2015; Singh et al., 2015, 2011; Xu et al., 2011; Yin et al., 2007). The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) has been well tolerated as a monotherapy in patients with recurrent GBM and exhibited modest single‐agent activity (Galanis et al., 2009).…”

“…Chromatin condensation, moreover, impairs recruitment of DNA repair factors and results in accumulation of DNA breaks. In the past several years, HDAC inhibitors have been used as radioand chemo-sensitizers in GBM (Lucio-Eterovic et al, 2008;Singh et al, 2015Singh et al, , 2011Xu et al, 2011). They induce differentiation, growth arrest and apoptosis in numerous malignant Figure 1 e Increased expression of HDAC1 and PARP1 in GBM cells correlates with higher level of SSBs and DSBs.…”

“…Data are shown as mean ± SD. ***p < 0.001; ****p < 0.0001. cells in vitro and in vivo (Eyupoglu et al, 2005;Komatsu et al, 2006;Min et al, 2015;Singh et al, 2015Singh et al, , 2011Xu et al, 2011;Yin et al, 2007). The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) has been well tolerated as a monotherapy in patients with recurrent GBM and exhibited modest singleagent activity (Galanis et al, 2009).…”

Deregulation of Histone-Modifying Enzymes and Chromatin Structure Modifiers Contributes to Glioma Development

“…Inhibitors of histone methyltransferases: chaetocin (targets SUV39H), BIX01294 (targets G9a/EHMT2) and 3-deazaneplanocin (targets EZH2) reduced cell viability, and chaetocin and BIX01294 induced apoptosis in glioma cells in vitro [84]. Combination of vorinostat and a KDM1 inhibitor tranylcypromine reduced cell viability of glioma initiating cells and displayed the high efficacy in the induction of the apoptosis-related genes in vitro and in a U87 xenograft model [93]. EZH2 inhibitors have therapeutic potential in tumors with mutated or overexpressed EZH2 [38].…”