Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

• Main Authors: Anahid Ehteda, Sandy Simon, Laura Franshaw, Federico M. Giorgi, Jie Liu, Swapna Joshi, Jourdin R.C. Rouaen, Chi Nam Ignatius Pang, Ruby Pandher, Chelsea Mayoh, Yujie Tang, Aaminah Khan, Caitlin Ung, Ornella Tolhurst, Anne Kankean, Elisha Hayden, Rebecca Lehmann, Sylvie Shen, Anjana Gopalakrishnan, Peter Trebilcock, Katerina Gurova, Andrei V. Gudkov, Murray D. Norris, Michelle Haber, Orazio Vittorio, Maria Tsoli, David S. Ziegler
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: Cell Reports
• Subjects: DIPG; brainstem glioma; H3K27M; facilitates chromatin transcription complex; HDAC; EZH2
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721003089
• ISSN: 2211-1247

Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.