title: RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer.
abstract: OBJECTIVE
  The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination.
  
  
  METHODS
  HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing.
  
  
  RESULTS
  The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines.
  
  
  CONCLUSIONS
  Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides 'proof-of-principle' for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy.
authors: Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Prakash
authors: P
authors: Vishnu
authors: Gerardo
authors: G
authors: Colon-Otero
authors: Gregory T
authors: GT
authors: Kennedy
authors: Laura A
authors: LA
authors: Marlow
authors: William P
authors: WP
authors: Kennedy
authors: Kevin J
authors: KJ
authors: Wu
authors: Joseph T
authors: JT
authors: Santoso
authors: John A
authors: JA
authors: Copland
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D034261:Epothilones / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000077210:Sunitinib; D015854:Up-Regulation; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
chemical_list: D034261:Epothilones; D007211:Indoles; D011758:Pyrroles; D020743:rhoB GTP-Binding Protein; C430592:ixabepilone; D000077210:Sunitinib