title: Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in microRNA expression.
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 treatments. We identified that panobinostat/everolimus combination resulted in enhanced anti-tumor activity mediated by decreased tumor growth concurrent with augmentation of p21 and p27 expression and the attenuation of angiogenesis and tumor proliferation via androgen receptor, c-Myc and HIF-1α signaling. Also, we observed altered expression of microRNAs associated with these three transcription factors. Overall, our results demonstrate that low dose concurrent panobinostat/everolimus combination therapy is well tolerated and results in greater anti-tumor activity compared to single treatments in tumor bearing immuno-competent mice. Finally, our results suggest that response of selected miRs could be utilized to monitor panobinostat/everolimus in vivo activity.
authors.affiliation: Roswell Park Cancer Institute, Genitourinary Program, Grace Cancer Drug Center, Buffalo, New York, United States of America.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.forename: Kristin
authors.initials: K
authors.lastname: Lehet
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Remi
authors.initials: R
authors.lastname: Adelaiye
authors.forename: Kiersten M
authors.initials: KM
authors.lastname: Miles
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000860:Hypoxia / Q000378:metabolism*; D007211:Indoles; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D000077767:Panobinostat; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D035683:MicroRNAs; D011944:Receptors, Androgen; D000077767:Panobinostat; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references.citation: Prostate. 2011 Feb 15;71(3):326-31
references.pmid: 20842666
references.citation: Cancer Invest. 2011 May;29(4):318-24
references.pmid: 21345070
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):141-53
references.pmid: 20028765
references.citation: Cell Oncol. 2010;32(1-2):11-27
references.pmid: 20203370
references.citation: Genes Dev. 2002 Oct 1;16(19):2530-43
references.pmid: 12368264
references.citation: Nat Rev Cancer. 2006 Sep;6(9):729-34
references.pmid: 16915295
references.citation: Int J Oncol. 2008 Jun;32(6):1293-303
references.pmid: 18497991
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):634-42
references.pmid: 16428510
references.citation: Curr Opin Oncol. 2010 Nov;22(6):592-7
references.pmid: 20739888
references.citation: Endocr Relat Cancer. 2010 Jan 29;17(1):F1-17
references.pmid: 19779034
references.citation: Oncogene. 2005 Nov 14;24(50):7465-74
references.pmid: 16288293
references.citation: Cancer Res. 2010 Jun 15;70(12):4820-8
references.pmid: 20516112
references.citation: Epigenetics. 2008 Nov;3(6):300-9
references.pmid: 19029799
references.citation: Adv Anat Pathol. 2008 Nov;15(6):319-31
references.pmid: 18948763
references.citation: Urol Oncol. 2010 Mar-Apr;28(2):134-8
references.pmid: 19523861
references.citation: Blood. 2009 Jul 9;114(2):380-93
references.pmid: 19383971
references.citation: Cancer Res. 2009 Feb 1;69(3):958-66
references.pmid: 19176386
references.citation: Prostate. 2010 Sep 15;70(13):1429-36
references.pmid: 20687216
references.citation: Anticancer Res. 2010 Oct;30(10):3895-901
references.pmid: 21036700
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Cancer Treat Rev. 2009 Nov;35(7):553-62
references.pmid: 19559538
references.citation: Clin Cancer Res. 2011 May 1;17(9):2863-73
references.pmid: 21415218
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3589-97
references.pmid: 18519793
references.citation: Cancer Cell. 2003 Nov;4(5):343-8
references.pmid: 14667501
references.citation: Pharmaceuticals (Basel). 2010 Aug 1;3(8):2411-2469
references.pmid: 21151768
references.citation: Urology. 2010 Apr;75(4):786-92
references.pmid: 19854473
references.citation: Leukemia. 2011 Jul;25(7):1064-79
references.pmid: 21436840
references.citation: Cancer Lett. 2009 Aug 8;280(2):233-41
references.pmid: 19344997
references.citation: Mol Cancer Ther. 2008 Jun;7(6):1347-54
references.pmid: 18566209
references.citation: Prostate. 2012 May 1;72(6):587-91
references.pmid: 21796655
references.citation: Mol Cancer Ther. 2003 Feb;2(2):151-63
references.pmid: 12589032
references.citation: Cancer Res. 2009 Sep 15;69(18):7165-9
references.pmid: 19738047
references.citation: Clin Cancer Res. 2004 Mar 1;10(5):1813-25
references.pmid: 15014036
references.citation: Int J Oncol. 2008 Aug;33(2):375-80
references.pmid: 18636159
references.citation: Nat Rev Cancer. 2008 Jul;8(7):497-511
references.pmid: 18563191
references.citation: Cell. 2000 Oct 13;103(2):253-62
references.pmid: 11057898
references.citation: Cell Cycle. 2007 Jun 15;6(12):1426-31
references.pmid: 17582223
references.citation: Br J Cancer. 2010 Sep 28;103(7):1001-7
references.pmid: 20842117
references.citation: Nature. 2005 Jun 9;435(7043):839-43
references.pmid: 15944709
references.citation: Cancer Res. 2009 Oct 1;69(19):7803-10
references.pmid: 19773438
references.citation: J Urol. 2010 Dec;184(6):2557-64
references.pmid: 21030039
references.citation: Oncogene. 2008 Jan 31;27(6):732-40
references.pmid: 17653085
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4500-10
references.pmid: 18628465
references.citation: Mod Pathol. 2008 Sep;21(9):1156-67
references.pmid: 18567993
references.citation: Cancer Res. 2005 Dec 15;65(24):11565-71
references.pmid: 16357166
references.citation: J Cell Mol Med. 2008 Sep-Oct;12(5A):1456-65
references.pmid: 18624768
references.citation: Cancer Res. 2004 Sep 15;64(18):6626-34
references.pmid: 15374977
references.citation: Life Sci. 2011 Feb 28;88(9-10):418-24
references.pmid: 21192952
references.citation: J Clin Oncol. 2005 Nov 10;23(32):8253-61
references.pmid: 16278481
references.citation: Cancer. 2009 Dec 1;115(23):5541-9
references.pmid: 19711464
references.citation: Cancer Cell. 2003 Sep;4(3):223-38
references.pmid: 14522256
references.citation: Anticancer Res. 2010 Sep;30(9):3579-83
references.pmid: 20944140
references.citation: Cancer Res. 2006 Sep 1;66(17):8814-21
references.pmid: 16951198
references.citation: Cell Death Differ. 2008 Apr;15(4):667-71
references.pmid: 18219318
references.citation: J Clin Endocrinol Metab. 2003 Jul;88(7):2972-82
references.pmid: 12843129
references.citation: Cancer Res. 2004 Jan 15;64(2):689-95
references.pmid: 14744786
references.citation: Sci Signal. 2009 Apr 21;2(67):pe24
references.pmid: 19383975
references.citation: Oncogene. 2004 Apr 19;23(18):3189-99
references.pmid: 15094768