Vanderbilt-Ingram Cancer Center

MMC/VICC Partnership : Research

COX-1 AND HDAC Inhibitors Suppress Ovarian Cancer Growth in Vitro and in Vivo

CO-LEADERS

• Meharry Co-Leader
  Dineo Khabele, M.D. – Assistant Professor of Obstetrics and Gynecology
  DKhabele@MMC.edu
• Vanderbilt Co-Leader
  Sudhansu K. Dey, Ph.D. – Dorothy Overall Wells Professor of Pediatrics and Professor of Cell and Developmental Biology and Pharmacology
  SK.Dey@Vanderbilt.edu

Ovarian cancer is the leading cause of death among gynecologic cancers in the United States.  We have demonstrated that cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. We have also shown histone deacetylases (HDACs) to be highly expressed in ovarian malignancies.  The goal of this research is to determine if inhibition of COX-1 and HDACs prevent tumor growth in ovarian cancers.  We hypothesize that cyclooxygenase (COX) inhibitors and HDAC inhibitors are synergistic in reducing tumor growth and size in ovarian cancers and that COX-1 and HDACs are targets for therapy in ovarian cancer.  In the proposed project we propose to evaluate the effects of COX-1 inhibition in combination with HDAC inhibition on ovarian cancer tumor growth in vitro and in vivo.  In vitro experiments will be performed with the established ovarian cancer cell lines, OVCAR3 and SKOV3.  Parallel in vivo experiments will be performed in RAG2/γ-C mice injected with ovarian cancer cell lines OVCAR3 and SKOV3.  The ovarian cancer cells and the mice will be evaluated in four treatment groups:

1. no treatment or vehicles as a negative control;
2. SC-560 (a COX-1 selective inhibitor);
3. FK228 (a potent HDAC inhibitor); and
4. both SC-560 and FK228. 

We will study the cellular and gene response to each treatment group with growth and apoptosis assays in vitro, and we will measure expression levels of COX-1, COX-2, HDAC 1, 2, 4 and 6 by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis in vitro and in vivo.  We also propose to expand the results of our preliminary data and findings in Specific Aim 1 to patient samples utilizing tissue arrays to evaluate the expression of COX-1 and HDACs.   For this aim we will create custom tissue arrays from paraffin blocks obtained from archived ovarian tissues collected from the collaborating institutions.  Specimens will be obtained from normal ovaries, benign ovarian tumors, and malignant ovarian tumors.  We will perform immunohistochemical staining of COX-1, COX-2, HDAC 1, 2, 4 and 6 protein expression and will relate results of the IHC staining to tumor histology, stage, and grade as well as the survival of each patient.