Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma.

Autor:	Singh AR; Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California., Joshi S; Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California., Burgoyne AM; Division of Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California., Sicklick JK; Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California., Ikeda S; Division of Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California., Kono Y; Division of Hepatology, Department of Medicine, University of California San Diego, La Jolla, California., Garlich JR; SignalRx Pharmaceuticals, San Diego, California., Morales GA; SignalRx Pharmaceuticals, San Diego, California., Durden DL; Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California. ddurden@ucsd.edu.; SignalRx Pharmaceuticals, San Diego, California.; Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, University of California San Diego Health System, La Jolla, California.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Nov; Vol. 15 (11), pp. 2553-2562. Date of Electronic Publication: 2016 Aug 05.
DOI:	10.1158/1535-7163.MCT-15-0976
Abstrakt:	Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual "first-in-class" PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib. Mol Cancer Ther; 15(11); 2553-62. ©2016 AACR. Competing Interests: of Potential Conflict of Interest No potential conflicts of interest were disclosed by the other authors. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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