Abstract 3189: Targeting NPM1 for controlling growth of Ewing sarcoma

Abstract

Ewing sarcoma is a rare cancer found in children and young adults. Long term survival rates are approximately 70% for patients who present without clinically overt metastases. However, 5 year survival is less than 20% for patients with recurrent tumors or metastasis. Thus, there is a need to improve local tumor control and to treat metastatic disease. Eighty five percent of these cancers are driven by the reciprocal chromosomal translocation t (11;22) (q24;q12), a consequence of a fusion between the 5' portion of Ewing sarcoma breakpoint region 1 on EWSR1 (chromosome 22) and the 3' portion of Friend leukemia virus integration site 1 on FLI1 (chromosome 11). Nucleophosmin1 (NPM1) is a chaperone protein involved in many cellular functions, including DNA repair. NPM1 has been shown to be a novel prognostic biomarker for patients with localized Ewing's sarcoma. Overall survival is significantly lower for patients whose tumors express high levels of NPM1. Besides promoting repair of DNA double strand breaks NPM1 directly interacts with and induces c-Myc-induced hyperproliferation and transformation. Consistent with this knowledge is the observation that relapsed Ewing's patients exhibit high levels of c-Myc expression compared to disease-free patients. Therefore, we wanted to ascertain whether NPM1 represented a molecular target for controlling growth of Ewing's sarcoma. CRISPR/Cas9-mediated targeting of NPM1 exons 3 and 4, as well as lentivirus-mediated shRNA targeting of NPM1 mRNA revealed that targeting of NPM1 expression reduced survival (colony formation) of TC32 and A673 cells (P<0.05). NPM shRNA also reduced TC32 sphere formation under non-adherent conditions. YTR107 and NSC348884 are small molecule inhibitors of NPM1 oligomerization, which is required for NPM1 activity. Both drugs reduced survival of TC32 and A673 Ewing's sarcoma cells in a dose-dependent fashion (P<0.05). We interpret these data to indicate that NPM1 represents a potential molecular target for controlling growth of Ewing's sarcoma. Supported in part by RO1CA140409. Citation Format: Geri Traver, Konjeti R. Sekhar, Narsimha R. Renthala, Peter A. Crooks, Maxwell Ofori, Michael L. Freeman. Targeting NPM1 for controlling growth of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3189.