Abstract IA16: Targeting cancer stem cells to overcome chemotherapy resistance

Abstract

Abstract While most ovarian cancer patients will have a complete response with surgery and chemotherapy, the majority will relapse and die of their disease. The high relapse rate in ovarian cancer after complete clinical response is highly consistent with a cancer stem-like cell (CSC) model. The CSC hypothesis suggests that only rare, inherently chemoresistant cancer cells with stem cell like characteristics are capable of proliferating and differentiating to regenerate the various cell types within a tumor, thereby causing relapse of the disease. In theory and in experimental models, the elimination of CSC can overcome chemotherapy resistance. We are developing novel therapies to specifically target ovarian CSC (OvCSC). Aldehyde Dehydrogenase (ALDH) enzymatic activity was one of the first, and remains one of the best supported CSC markers. ALDH enzymes perform numerous critical functions including the biosynthesis of retinoic acid. Our group and others have found that ALDH identifies a population cancer cells with ovarian CSC (OvCSC) activity. Primary human ALDH+ cells initiate and propagate tumors in mice while ALDH-cells do not. ALDH used in combination with the stem cell marker CD133 enriches CSC isolation. ALDH1A+ or ALDH1A1+CD133+ cells in primary tumor samples predict poor prognosis for ovarian cancer patients [9, 11]. ALDH and CD133 are enriched in tumor specimens immediately following chemotherapy [12]. ALDH1A1 is 100 fold upregulated in chemoresistant ovarian cancer cells and ALDH1A knockdown restores chemosensitivity. Finally, normal ovary epithelial stem cells also express ALDH and CD133, and when mutated for p53 and Rb, these cells gain CSC capacity and initiate serous tumors. Taken together these data strongly support a role for ALDH in serous ovarian CSC. Based on the CSC specific function of ALDH and the function of we generated and screened. We have therefore identified and screened dozens of ALDH inhibitors and molecular analogs of known ALDH inhibitors. Using cell lines with well-defined CSC populations, we have identified several compounds which kill cells expressing CSC markers in vitro. CSC die via necrosis. Lead compounds prevent tumor sphere formation in vitro and restrict tumor initiation in vivo. The novel ALDH inhibitors are highly synergistic with chemotherapy and reverse chemotherapy resistance in primary human tumor xenografts. Taken together our data support ALDH as a CSC specific target and identifies novel compounds as potential new therapeutics. Citation Format: Ronald J. Buckanovich. Targeting cancer stem cells to overcome chemotherapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA16.