Dual HDAC and PI3K Inhibition Abrogates NFκB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas

Abstract

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG. These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. .

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

“…In glioblastoma, FOXM1 has been shown to promote stemness by modulating SOX2 expression in vitro and in vivo [67], and in neuroblastoma cells, FOXM1 was shown to directly activate SOX2 expression [71]. After treatment with a dual HDAC and PI3K inhibitor in high grade pediatric glioma, the expression and transcriptional activity of FOXM1 decreased [72], which is consistent with our finding that FOXM1 expression was altered.…”

The p53 Pathway in Glioblastoma

“…When HDAC6 is absent or inhibited, the complex is disrupted resulting the dissociation and degradation of the mut-p53 [ 67 ]. Several HDAC inhibitors, including CUDC-907, CCNU, CUDC-and vorinostat, have been tested in GBM cells and mouse models [ 138 , 139 , 140 , 141 ]. Singh and colleagues reported that an FDA-approved HDAC inhibitor vorinostat in combination with tranylcypromine, can reduce GBM stem cell viability in a GBM xenograft model and lead to changes in apoptosis-regulatory genes such as TP53 and TP73 [ 141 ].…”

The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in Small Cell Lung Cancer

“…Therefore, these studies demonstrated that identifying multiple-targeted drugs may expand treatment effects. CUDC-907, a dual inhibitor of PI3K and HDAC that targeting class PI3Ks as well as class and class ‖ HDAC has shown remarkable anti-tumor e cacy in multiple cancer types [20,21,22,33]. However, the effect of CUDC-907 has not been investigated in SCLC.…”