Am J Cancer Res 2013;3(4):390-401

Original Article
Preclinical evaluation of the mTOR inhibitor, temsirolimus, in combination with
the epothilone B analog, ixabepilone in renal cell carcinoma

Christina A von Roemeling, Laura A Marlow, William P Kennedy, Gregory T Kennedy, John A Copland, Michael E Menefee

Department of Cancer Biology, Department of Hematology and Oncology, Mayo Clinic College of Medicine, 4500 San Pablo
Road, Jacksonville, Florida, 32224. These authors have contributed equally to the work.

Received July 14, 2013; Accepted August 6, 2013; Epub August 14, 2013; Published August 30, 2013

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. (ajcr0000216).

Keywords: Renal cell carcinoma, ixabepilone, microtubule stabilizer, mTOR inhibitor, temsirolimus, combination therapy

Address correspondence to: Michael E Menefee, Department of Hematology and Oncology, Mayo Clinic College of Medicine,
4500 San Pablo Road, Jacksonville, Florida 32224. Tel: 904-953-7290; Fax: 904-953-2315; E-mail:
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American Journal of Cancer Research
ISSN: 2156-6976