Angeliki Andrikopoulou1,2, Michalis Liontos1,2, Konstantinos Koutsoukos1,2, Meletios-Athanasios Dimopoulos1,2, Flora Zagouri3,4. 1. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 11528, Athens, Greece. 2. School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528, Athens, Greece. 3. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 11528, Athens, Greece. florazagouri@yahoo.co.uk. 4. School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528, Athens, Greece. florazagouri@yahoo.co.uk.
Abstract
BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. CONCLUSIONS: BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.
BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. CONCLUSIONS:BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.
Entities:
Keywords:
BET inhibitors; BET proteins; Bromodomain; Epigenetic treatment; High-grade serous carcinoma; Ovarian cancer
Authors: Nishan H Chobanian; Victoria L Greenberg; Jennifer M Gass; Christopher P Desimone; John R Van Nagell; Stephen G Zimmer Journal: Anticancer Res Date: 2004 Mar-Apr Impact factor: 2.480
Authors: Panagis Filippakopoulos; Jun Qi; Sarah Picaud; Yao Shen; William B Smith; Oleg Fedorov; Elizabeth M Morse; Tracey Keates; Tyler T Hickman; Ildiko Felletar; Martin Philpott; Shonagh Munro; Michael R McKeown; Yuchuan Wang; Amanda L Christie; Nathan West; Michael J Cameron; Brian Schwartz; Tom D Heightman; Nicholas La Thangue; Christopher A French; Olaf Wiest; Andrew L Kung; Stefan Knapp; James E Bradner Journal: Nature Date: 2010-09-24 Impact factor: 49.962
Authors: Garrett W Rhyasen; Yi Yao; Jingwen Zhang; Austin Dulak; Lillian Castriotta; Kelly Jacques; Wei Zhao; Farzin Gharahdaghi; Maureen M Hattersley; Paul D Lyne; Edwin Clark; Michael Zinda; Stephen E Fawell; Gordon B Mills; Huawei Chen Journal: PLoS One Date: 2018-07-23 Impact factor: 3.240
Authors: Jacob P Veenstra; Lucas Felipe Fernandes Bittencourt; Katherine M Aird Journal: Am J Physiol Cell Physiol Date: 2022-05-18 Impact factor: 5.282
Authors: Samuel P Boyson; Cong Gao; Kathleen Quinn; Joseph Boyd; Hana Paculova; Seth Frietze; Karen C Glass Journal: Cancers (Basel) Date: 2021-07-19 Impact factor: 6.639