concurrent hdac and mtorc1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in microrna expression并发hdac mtorc1抑制减弱雄激素受体和缺氧信号与微rna表达改变有关.pdf

Concurrent HDAC and mTORC1 Inhibition Attenuate Androgen Receptor and Hypoxia Signaling Associated with Alterations in MicroRNA Expression 1 1 1 1 1 2 Leigh Ellis , Kristin Lehet , Swathi Ramakrishnan , Remi Adelaiye , Kiersten M. Miles , Dan Wang , Song 2 3 4 1 Liu , Peter Atadja , Michael A. Carducci , Roberto Pili * 1 Roswell Park Cancer Institute, Genitourinary Program, Grace Cancer Drug Center, Buffalo, New York, United States of America, 2 Roswell Park Cancer Institute, Department of Bioinformatics, Buffalo, New York, United States of America, 3 Novartis Biomedical Research Institute, Shanghai, China, 4 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States of America Abstract Specific inhibitors towards Histone Deacetylases (HDACs) and Mammalian Target of Rapamycin Complex 1 (mTORC1) have been developed and demonstrate potential as treatments for patients with advanced and/or metastatic and castrate resistant prostate cancer (PCa). Further, deregulation of HDAC expression and mTORC1 activity are documented in PCa and provide rational targets to create new therapeutic strategies to treat PCa. Here we report the use of the c-Myc adenocarcinoma cell line from the c-Myc transgenic mouse with prostate cancer to evaluate the in vitro and in vivo anti- tumor activity of the combination of the HDAC inhibitor panobinostat with the mTORC1 inhibitor everolimus. Panobinostat/ everolimus combination treatment resulted in significantly greater antitumor activity in mice bearing androgen sensitive Myc-CaP and castrate resistant Myc-CaP tumors compared to single tre