2. Academic Validation
  3. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

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

  • Cell Rep. 2021 Apr 13;35(2):108994. doi: 10.1016/j.celrep.2021.108994.
Anahid Ehteda 1,  Sandy Simon 1,  Laura Franshaw 1,  Federico M Giorgi 2,  Jie Liu 1,  Swapna Joshi 1,  Jourdin R C Rouaen 1,  Chi Nam Ignatius Pang 3,  Ruby Pandher 1,  Chelsea Mayoh 4,  Yujie Tang 5,  Aaminah Khan 1,  Caitlin Ung 1,  Ornella Tolhurst 1,  Anne Kankean 1,  Elisha Hayden 1,  Rebecca Lehmann 1,  Sylvie Shen 1,  Anjana Gopalakrishnan 1,  Peter Trebilcock 1,  Katerina Gurova 6,  Andrei V Gudkov 6,  Murray D Norris 7,  Michelle Haber 1,  Orazio Vittorio 4,  Maria Tsoli 8,  David S Ziegler 9
Affiliations

Affiliations

  • 1 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
  • 3 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
  • 4 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
  • 5 State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6 Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 7 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW, Australia.
  • 8 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: mtsoli@ccia.org.au.
  • 9 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia; Kid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic address: d.ziegler@unsw.edu.au.
PMID: 33852836 DOI: 10.1016/j.celrep.2021.108994
Abstract

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.

Keywords

DIPG; E2F1; EZH2; H3K27M; HDAC; anticancer therapy; brainstem glioma; facilitates chromatin transcription complex; pediatric cancer; xenograft model.

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