Abstract
Abstract Bromodomain and extra-terminal (BET) family are dual bromodomain-containing proteins that play an important role in transcription regulation. ABBV-075 is a small molecule BET bromodomain inhibitor currently in phase 1 clinical trials. Here we report the identification of Hexim1 and other BET-responsive genes as robust pharmacodynamic markers for monitoring ABBV-075 target engagement in tumors and in surrogate tissues such as whole blood and skin. Transcription profiling of cancer cell lines for their responses to BET inhibitors identified a set of 9 BET-regulated genes, including Hexim1, that responded to BET inhibition across cancer cell lines and in xenograft tumors. Further characterization of BET-responsive genes in surrogate tissues such as mouse skin, mouse/human PBMCs and whole blood revealed that the mRNA level of Hexim1 exhibited the best response to BETi treatment across different settings. A dose-dependent increase of Hexim1 expression was detected in the whole blood of ABBV-075 treated tumor bearing mice, and the Hexim1 response was closely correlated with the plasma drug concentration and largely reflected the anti-tumor efficacy at various dose levels of ABBV-075. Hexim1 is part of a protein/RNA complex that sequesters pTEFb and prevents its recruitment by BRD4. It also reportedly mediates the anti-proliferative activity of BRD4 in AML. Taken together, Hexim1 could serve as a functional relevant pharmacodynamic marker for monitoring ABBV-075 target engagement in animal models and in the clinical setting. Citation Format: Xiaoli Huang, Xiaoyu Lin, Leiming Li, Rongqi Wang, Lisa Roberts, Paul Hessler, Tamar Uziel, Lloyd Lam, Terry Magoc, Daniel H. Albert, Steven W. Elmore, Guowei Fang, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. HEXIM1 as a pharmacodynamic marker for monitoring target engagement of ABBV-075. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3770.
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