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Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic by Ulrike Tontsch-Grunt; Paula-Elena Traexler; Anke Baum; Hanny Musa; Kristell Marzin; Shaonan Wang; Francesca Trapani; Harald Engelhardt; Flavio Solca is a Medicine article available to read on EtoBox.
What is Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic about?
## Abstract ## Background BET inhibitors have been tested in several clinical trials where, despite encouraging preclinical results, substantial clinical benefit in monotherapy remains limited. This work illustrates the translational challenges and reports new data around the novel BET inhibitor, BI 894999. At clinically achievable concentrations, mechanistic studies were carried out to study pathway modulation and rational drug combinations. ## Methods BRD-NUT fusions are oncogenic drivers in NUT carcinoma (NC). The effects of BI 894999 on proliferation, chromatin binding and pathway modulation were studied in NC in vitro. These studies were complemented by efficacy studies either as a single agent or in combination with the clinical p300/CBP inhibitor CCS1477. ## Results Based on the modelling of preclinical and clinical data, we proposed and implemented a new clinical scheduling regimen. This led to plasma levels sufficient to fully dislodge BRD-NUT from chromatin and to sustained and pronounced pharmacodynamic (PD) modulation of HEXIM1 and HIST2H2BF. Platelet counts in patient blood samples were improved compared to previous schedules. Rational combination studies of BI 894999
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- Author
- Ulrike Tontsch-Grunt; Paula-Elena Traexler; Anke Baum; Hanny Musa; Kristell Marzin; Shaonan Wang; Francesca Trapani; Harald Engelhardt; Flavio Solca
- Publisher
- Springer Science and Business Media LLC
- Published
- 2022
- Language
- EN
- Field
- Medicine (Health Sciences)