Abstract 4274: High aldehyde dehydrogenase activity identifies a chemotherapy-resistant population of ewing's sarcoma cells with a stem cell phenotype that retains sensitivity to EWS-FLI1 inhibition

Abstract

Abstract Ewing's sarcoma family tumors (ESFT) are the second most common bone tumors in children and young adults. Despite being quite responsive to chemotherapy, patients with localized disease have a 30% recurrence rate, and 80% of patients with metastatic disease die within 5 years of diagnosis. The expression of the EWS-FLI1 fusion protein as a result of chromosomal translocation (11; 22) (q24; q12) is crucial for initiation and maintenance of the tumor; however, the mechanism by which EWS-FLI1 mediates neoplastic transformation is poorly understood. RNA helicase A (RHA) physically interacts with EWS-FLI1, modulating its oncogenic activity. The cancer stem cell hypothesis proposes that tumors originate from and are maintained by a small subset of chemotherapy-resistant stem cells. Thus, identification of Ewing's sarcoma stem cells will lead to the development of targeted therapies that should improve the treatment of patients with this disease. We attempted to identify a population of Ewing's sarcoma cells with stem cell properties (self-renewal in vitro, clonogenic activity, and tumor initiating activity in immunodeficient mice) based on high aldehyde dehydrogenase (ALDHhigh) activity. The ALDHhigh population was enriched for stem cell activity (compared to the ALDHlow cells) as defined by these assays, and was resistant to standard chemotherapy drugs to treat sarcomas (doxorubicin and etoposide). Both populations expressed EWS-FLI1. We then investigated whether a novel small molecule, YK-4-279, which specifically targets the RHA/EWS-FLI1 interaction, is toxic to the chemotherapy-resistant ALDHhigh cells. We found that the ALDHhigh cells retain sensitivity YK-4-279. Our data demonstrate that ESFT cells that express high levels of ALDH have stem-like properties, and, combined with evidence that YK-4-279 inhibits the growth of ESFT xenografts in mice, provide support for a novel approach to ESFT therapy. This approach should improve the survival of patients with these tumors in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4274.