Abstract B26: Novel lncRNA regulates PAX3/FOXO1 expression and is essential for RMS tumorigenesis

Abstract

Abstract Rhabdomyosarcoma (RMS) is a pediatric cancer of the developing skeletal muscle, and the mechanisms that drive this tumor are not completely understood. Despite the genetic alterations discovered in this disease, therapeutics targeting these mutations have not improved patient survival over the past 25 years. Since more than 60% of patients with metastatic disease do not survive, this creates an urgency to identify new vulnerabilities to exploit for therapeutic development. To do this we performed a comprehensive evaluation of the epigenomic landscape across 16 RMS orthotopic patient-derived xenograft tumors. We identified 41 super enhancers unique to RMS tumors. Within these, we discovered 9 novel lncRNAs of which 3 have potential cis-regulatory activity. We hypothesize that these lncRNAs are required for RMS tumorigenesis. Indeed, from preliminary knockdown analysis of one of these lncRNAs, lnc19_31, we observed rapid cell death in RMS cell lines and concomitant upregulation of apoptotic genes based on RNA-seq, such as TP53. Remarkably, we also observed more than 70 cancer consensus genes that were up- or downregulated, including genes that are frequently mutated in RMS patients such as BCOR and FGFR4. Within these we were excited to discover the loss of PAX3/FOX1 translocation, as this is a major driver of the alveolar subtype and often associated with poor prognosis. Taken together, we hypothesize that lncRNA deregulation is required for expression of key oncogenes and tumor suppressor and essential for RMS cell survival and tumorigenesis. These data will shed insight into a new underlying mechanism that drives this disease. These exciting findings present potential tumor vulnerabilities and, thus, new opportunities for future therapeutic discoveries that would otherwise be beyond our reach. Citation Format: Xiang Chen, Mireya Herrera-Herrera, Justina McEvoy. Novel lncRNA regulates PAX3/FOXO1 expression and is essential for RMS tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B26.