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

被引：39

作者：

Ehteda, Anahid ^{[1
]}

Simon, Sandy ^{[1
]}

Franshaw, Laura ^{[1
]}

Giorgi, Federico M. ^{[2
]}

Liu, Jie ^{[1
]}

Joshi, Swapna ^{[1
]}

Rouaen, Jourdin R. C. ^{[1
]}

Pang, Chi Nam Ignatius ^{[3
]}

Pandher, Ruby ^{[1
]}

Mayoh, Chelsea ^{[1
,7
]}

Tang, Yujie ^{[4
]}

Khan, Aaminah ^{[1
]}

Ung, Caitlin ^{[1
]}

Tolhurst, Ornella ^{[1
]}

Kankean, Anne ^{[1
]}

Hayden, Elisha ^{[1
]}

Lehmann, Rebecca ^{[1
]}

Shen, Sylvie ^{[1
]}

Gopalakrishnan, Anjana ^{[1
]}

Trebilcock, Peter ^{[1
]}

Gurova, Katerina ^{[5
]}

Gudkov, Andrei, V ^{[5
]}

Norris, Murray D. ^{[1
,6
]}

Haber, Michelle ^{[1
]}

Vittorio, Orazio ^{[1
,7
]}

Tsoli, Maria ^{[1
,7
]}

Ziegler, David S. ^{[1
,7
,8
]}

机构：

[1] Univ New South Wales, Lowy Canc Res Ctr, Childrens Canc Inst, Sydney, NSW, Australia

[2] Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy

[3] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia

[4] Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol,State Key Lab Oncogenes & Relat, Key Lab Cell Differentiat & Apoptosis,Natl Minist, Shanghai 200025, Peoples R China

[5] Roswell Park Comprehens Canc Ctr, Dept Cell Stress Biol, Buffalo, NY USA

[6] Univ New South Wales, Ctr Childhood Canc Res, Sydney, NSW, Australia

[7] Univ New South Wales, Sch Womens & Childrens Hlth, Sydney, NSW, Australia

[8] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia

来源：

CELL REPORTS | 2021年 / 35卷 / 02期

基金：

英国医学研究理事会;

关键词：

PEDIATRIC HIGH-GRADE; RB/E2F PATHWAY; CELL; MUTATIONS; GENES; EZH2; PROLIFERATION; INHIBITION; QUINACRINE; NUCLEOSOME;

D O I：

10.1016/j.celrep.2021.108994

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页数：21

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