Abstract IA05: Targeting the oxidative stress pathway in rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Histologically, there are two major subtypes of rhabdomyosarcoma, embryonal and alveolar, which have distinct clinical, molecular, and genetic features. Patients with resected localized disease are highly curable, but patients with recurrent, metastatic or large unresectable tumors have a poor clinical outcome. In this study, we performed whole-genome sequencing, exome sequencing, RNA-sequencing and DNA methylation profiling of embryonal and alveolar rhabdomyosarcomas. The embryonal tumors had more structural and copy number variations than did alveolar tumors and those lesions result from the accumulation of chromosomal lesions over time. Mutations in the RAS/NF1 pathway were significantly associated with intermediate- and high-risk embryonal rhabdomyosarcoma. In contrast, alveolar rhabdomyosarcoma had fewer genetic lesions overall and there were no known cancer consensus genes that were recurrently mutated other than the PAX3/7-FOXO1translocation that is a hallmark of alveolar rhabdomyosarcoma. DNA methylation profiling and RNA-seq analysis showed that embryonal and alveolar rhabdomyosarcomas are distinct and the alveolar tumors more closely resemble normal myoblasts and myotubes. To identify novel therapeutics for embryonal rhabdomyosarcomas, we developed and characterized 6 orthotopic xenografts of tumors in our discovery cohort. High throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for embryonal rhabdomyosarcoma. Citation Format: Michael A. Dyer. Targeting the oxidative stress pathway in rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA05.