Abstract 3737: Identifying novel therapeutic targets for cancer stem cell differentiation.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC A growing body of evidence supports a role for cancer stem cells in the initiation and maintenance of a wide range of tumors. Cancer stem cells appear to be less sensitive to current treatments, necessitating the discovery of novel strategies for targeting this cell type. We hypothesize that driving cancer stem cells to differentiate will be an effective approach for inhibiting tumor growth and recurrence. Indeed, this strategy is used for the treatment of Acute Promyelocytic Leukemia, which presents with an accumulation of promyelocytes. Treatment with all-trans retinoic acid drives these cells to differentiate into neutrophils and leads to complete remission in over 90% of patients. The goal of our work is to identify druggable nodes to drive epithelial cancer stem cells to differentiate, leading to inhibition of tumor growth. We are currently focused on colorectal cancer, for which there is a high unmet medical need. Each year, more than 1.2 million new cases of colorectal adenocarcinoma are reported. It is estimated that 80% of colon tumors have mutations in the adenomatous polyposis coli (APC) gene, which results in constitutive activation of the Wnt pathway and nuclear accumulation of β-catenin. Wnt signaling activates the transcription of genes that drive cell proliferation. Recent studies have shown that β-catenin is necessary for the maintenance of colorectal adenocarcinomas with APC mutations. Indeed, β-catenin knockdown in colon cancer cells drives them to differentiate and decreases their proliferative capacity, reducing tumor size in vivo. We have developed a number of methods to monitor this process in vitro, and will present our efforts to screen for novel targets that can drive colon tumor stem cells to differentiate. Citation Format: German L. Velez Reyes, Haidi Yang, Aaron Wilson, Martin Henault, Elizabeth Frias, Michael Schlabach, Margaret Mclaughlin, Nathan Ross, Gregory Hoffman, Amy Chen, Marc Hild, Aron Jaffe. Identifying novel therapeutic targets for cancer stem cell differentiation. [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 3737. doi:10.1158/1538-7445.AM2013-3737