CPI203, a BET inhibitor, down-regulates a consistent set of DNA synthesis genes across a wide array of glioblastoma lines.

in PloS one by Matthew C Garrett, Troy Carnwath, Rebecca Albano, Yonghua Zhuang, Catherine A Behrmann, Merissa Pemberton, Farah Barakat, Robert Lober, Mark Hoeprich, Anthony Paravati, Marilyn Reed, Hailey Spry, Daniel Woo, Eric O'Brien, Brett VanCauwenbergh, John Perentesis, Rani Nasser, Mario Medvedovic, David R Plas

TLDR

  • The study identified CPI203 as the most effective chromatin-modifying compound in treating glioblastoma, and suggests that BET inhibitors may be a promising approach for glioblastoma therapy.
  • The study highlights the potential of chromatin-modifying compounds to target glioblastoma growth pathways and identifies the most effective compounds and their associated gene targets.

Abstract

Glioblastomas utilize malignant gene expression pathways to drive growth. Many of these gene pathways are not directly accessible with molecularly targeted pharmacological agents. Chromatin-modifying compounds can alter gene expression and target glioblastoma growth pathways. In this study, we utilize a systematic screen of chromatin-modifying compounds on a panel of patient-derived glioblastoma lines to identify promising compounds and their associated gene targets. Five glioblastoma cell lines were subjected to a drug screen of 106 chromatin-modifying compounds representing 36 unique drug classes to determine the twelve most promising drug classes and the best candidate inhibitors in each class. These twelve drugs were then tested with a panel of twelve patient-derived gliomasphere lines to identify growth inhibition and corresponding gene expression patterns. Overlap analysis and weighted co-expression network analysis (WCGNA) were utilized to determine potential target genes and gene pathways. The initial drug screen identified twelve candidate pharmacologic agents for further testing. Drug sensitivity testing indicated an overall high degree of variability between gliomasphere lines. However, CPI203 was the most consistently effective compound, and the BET inhibitor class was the most consistently effective class of compounds across the gliomasphere panel. Correspondingly, most of the compounds tested had highly variable effects on gene expression between gliomasphere lines. CPI203 stood out as the only compound to induce a consistent effect on gene expression across different gliomasphere lines, specifically down-regulation of DNA-synthesis genes. Amongst the twelve tested cell lines, high expression of CDKN2A and CDKN2B distinguished more drug sensitive from more drug resistant lines. WCGNA identified two oncogenic gene modules (FBXO5 and MELK) that were effectively downregulated by CPI203 (FBXO5) and ML228 (FBXO5 and MELK). The bromodomain inhibitor CPI203 induced relatively consistent effects on gene expression and growth across a variety of glioblastoma lines, specifically down-regulating genes associated with DNA replication. We propose that clinically effective BET inhibitors have the potential to induce consistent beneficial effects across a spectrum of glioblastomas.

Overview

  • The study aims to identify chromatin-modifying compounds that can target glioblastoma growth pathways and identify the most effective compounds and their associated gene targets.
  • The study utilized a systematic screen of 106 chromatin-modifying compounds on 5 glioblastoma cell lines to identify the most promising compounds and their associated gene targets.
  • The study sought to determine the potential target genes and gene pathways affected by the most effective compounds and to identify the most effective class of compounds and the best candidate inhibitors in each class.

Comparative Analysis & Findings

  • The initial drug screen identified 12 candidate pharmacologic agents for further testing, with CPI203 being the most consistently effective compound across the gliomasphere panel.
  • The BET inhibitor class was the most consistently effective class of compounds across the gliomasphere panel.
  • CPI203 was the only compound to induce a consistent effect on gene expression across different gliomasphere lines, specifically down-regulating DNA-synthesis genes.

Implications and Future Directions

  • The study suggests that clinically effective BET inhibitors have the potential to induce consistent beneficial effects across a spectrum of glioblastomas.
  • Future studies should investigate the potential mechanisms of action of CPI203 and other BET inhibitors in glioblastoma, as well as their therapeutic potential in combination with other treatments.
  • The study highlights the need for further research to identify the most effective compounds and treatment strategies for glioblastoma, and to determine the optimal clinical trial designs for testing these compounds.
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