title: Preclinical evaluation of the mTOR inhibitor, temsirolimus, in combination with the epothilone B analog, ixabepilone in renal cell carcinoma.
abstract: Historically, metastatic renal cell carcinoma (mRCC) is more resistant to conventional cytotoxic chemotherapeutic agents than other solid tumors. Although significant progress has been made over the last decade with several novel therapeutics, these agents invariably go on to fail, largely due to either intrinsic or acquired resistance. To help overcome, or at least delay resistance, combinatorial therapies utilizing agents with disparate, and ideally complementary, mechanisms of actions are needed. In this report, we assess the novel combination of the mTOR inhibitor, temsirolimus, with the microtubule stabilizing drug ixabepilone in RCC. Our results demonstrate synergy in multiple cell lines of RCC and further evaluation of this combination is warranted in the clinical setting. Activation of the endoplasmic reticulum (ER) stress response pathway may in part explain the combinatorial synergy. We further propose that ER stress induced proteins may serve as early response biomarkers to combinatorial therapy in a clinical trial.
authors: Department of Cancer Biology, Mayo Clinic College of Medicine 4500 San Pablo Road, Jacksonville, Florida, 32224.
authors: Christina A
authors: CA
authors: von Roemeling
authors: Laura A
authors: LA
authors: Marlow
authors: William P
authors: WP
authors: Kennedy
authors: Gregory T
authors: GT
authors: Kennedy
authors: John A
authors: JA
authors: Copland
authors: Michael E
authors: ME
authors: Menefee
keywords: Renal cell carcinoma; combination therapy; ixabepilone; mTOR inhibitor; microtubule stabilizer; temsirolimus
references: J Cell Biol. 1986 Oct;103(4):1557-68
references: 3533956
references: Clin Cancer Res. 2007 Dec 15;13(24):7480-6
references: 18094432
references: Nephron Exp Nephrol. 2009;112(1):e1-9
references: 19342868
references: Cell Mol Life Sci. 2001 Dec;58(14):2069-84
references: 11814057
references: Indian J Urol. 2007 Jul;23(3):332-3
references: 19718348
references: J Biol Chem. 1997 Jan 24;272(4):2534-41
references: 8999970
references: Adv Enzyme Regul. 1984;22:27-55
references: 6382953
references: Nat Rev Clin Oncol. 2012 Apr 10;9(6):327-37
references: 22473096
references: Trends Cell Biol. 2012 May;22(5):274-82
references: 22444729
references: J Cell Biol. 1998 Mar 23;140(6):1277-80
references: 9508761
references: Cancer Res. 1995 Jun 1;55(11):2325-33
references: 7757983
references: Lancet. 2008 Aug 9;372(9637):449-56
references: 18653228
references: Int J Hepatol. 2013;2013:103830
references: 23509629
references: Annu Rev Biochem. 2000;69:277-302
references: 10966460
references: Nature. 1994 Jun 30;369(6483):756-8
references: 8008069
references: EMBO J. 1998 Nov 2;17(21):6168-77
references: 9799226
references: Clin Cancer Res. 2010 Mar 1;16(5):1634-41
references: 20179242
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: Nat Rev Mol Cell Biol. 2012 Jan 18;13(2):89-102
references: 22251901
references: Curr Probl Cancer. 1997 Jul-Aug;21(4):185-232
references: 9285186
references: Cancer Lett. 2010 Dec 8;298(2):195-203
references: 20673698
references: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references: 22237781
references: Cancer. 2007 Jun 1;109(11):2257-67
references: 17440983
references: Ann Oncol. 2011 Jan;22(1):145-148
references: 20595449
references: J Clin Oncol. 2005 Aug 10;23(23):5314-22
references: 15955899
references: PLoS One. 2012;7(10):e46726
references: 23077520
references: Cancer Manag Res. 2009 Jun 29;1:69-77
references: 21188125
references: Nat Protoc. 2008;3(6):1101-8
references: 18546601
references: Curr Biol. 1998 Jul 2;8(14):798-806
references: 9663388
references: J Clin Invest. 2005 Oct;115(10):2656-64
references: 16200199
references: J Urol. 2007 Jan;177(1):346-52
references: 17162089
references: JAMA. 1999 May 5;281(17):1628-31
references: 10235157
references: Nat Rev Cancer. 2004 May;4(5):335-48
references: 15122205
references: Breast Cancer Res Treat. 2010 Jun;121(2):261-71
references: 20229176
references: J Biol Chem. 2000 Sep 1;275(35):27013-20
references: 10856300
references: Clin Lung Cancer. 2012 May;13(3):171-80
references: 22133291
references: Oncologist. 2011;16 Suppl 2:14-22
references: 21346036
references: N Engl J Med. 2007 May 31;356(22):2271-81
references: 17538086
references: Cell Mol Life Sci. 2005 Dec;62(24):3039-56
references: 16314924
references: Br J Cancer. 2010 Aug 24;103(5):649-55
references: 20664591
references: Cancer Biol Ther. 2007 Apr;6(4):490-3
references: 17457044
references: Curr Opin Cell Biol. 2010 Apr;22(2):169-76
references: 19945836
references: Autophagy. 2010 Feb;6(2):239-47
references: 20104019