Abstract 3731: Targeting ovarian cancer stem cells using a novel ALDH inhibitor.

Abstract

Abstract Background: Cancer cells with stem cell-like properties (CSC) are resistant to chemotherapy and are believed to be the source of cancer recurrence. Aldehyde dehydrogenase enzymatic activity (ALDH), alone and in combination with the stem cell marker CD133, can be used to define a hierarchy of Ovarian Cancer Stem Cells (OvCSC). ALDH is functionally important for stem cells, regulating motile cellular metabolic functions and the biosynthesis of retinoic acid. ALDH agonists have been demonstrated to enhance ‘stemness’ in some tissues. We therefore sought to determine the impact of ALDH antagonist on OvCSC. Methods and Results: We screened a variety of novel derivatives with confirmed or potential ALDH activity based on the molecular homology to the known ALDH inhibitor DEAB. Using the ALDEFLUOR assay and A2780 cancer cell line as a source of ALDH+CD133+ cells, we identified a lead compound 673 which effectively inhibits ALDH activity. Interestingly this compound also potently depletes CD133+ ovarian cancer cells. Supporting functional depletion of OvCSC, treatment of primary human ovarian tumor ascites cells with 673 resulted in 4-20 fold decrease tumor sphere formation. 673 treatment is highly synergistic with cisplatin both in-vitro and in-vivo as assessed by cell growth curves and tumor growth. Importantly, pre-treatment of tumor cells with 673 significantly reduced tumor in tumor initiation and growth rates. Finally, 673 is non-toxic to normal stem cells. Conclusions: We have identified a novel ALDH inhibitor, 673, which depletes the ovarian cancer cells expressing CSC markers. CSC marker independent functional assays, with both cell lines and primary human ovarian cancer cells, indicate 673 is depleting OvCSC activity. Thus this may be a powerful new therapeutic approach to target CSC. Future studies will elucidate the molecular mechanism that underlies 673 OvCSC depletion activities as well as to identify a specific ALDH isoforms targeted in ovarian cancer. Citation Format: Ilana Chefetz, Kun Yang, Scott D. Larsen, Ronald J. Buckanovich. Targeting ovarian cancer stem cells using a novel ALDH inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3731. doi:10.1158/1538-7445.AM2013-3731