Cell Reports (Apr 2021)
Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG
- 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
Affiliations
- Anahid Ehteda
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Sandy Simon
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Laura Franshaw
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Federico M. Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Jie Liu
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Swapna Joshi
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Jourdin R.C. Rouaen
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Chi Nam Ignatius Pang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
- Ruby Pandher
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Chelsea Mayoh
- 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
- Yujie Tang
- 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
- Aaminah Khan
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Caitlin Ung
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Ornella Tolhurst
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Anne Kankean
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Elisha Hayden
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Rebecca Lehmann
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Sylvie Shen
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Anjana Gopalakrishnan
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Peter Trebilcock
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Katerina Gurova
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Andrei V. Gudkov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Murray D. Norris
- 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
- Michelle Haber
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Orazio Vittorio
- 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
- Maria Tsoli
- 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; Corresponding author
- David S. Ziegler
- 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; Corresponding author
- Journal volume & issue
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Vol. 35,
no. 2
p. 108994
Abstract
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.
