Abstract 232: PAX3-FOXO1a target genes in alveolar rhabdomyosarcoma: Possible therapeutic targets

Abstract

Abstract Rhabdomyosarcoma (RMS) is a pediatric soft tissue tumor that is derived from skeletal muscle and expresses many muscle specific proteins. Most commonly RMS presents in one of two histological subtypes; Embryonal RMS (ERMS) or Alveolar RMS (ARMS). The ARMS subtype is more aggressive, more prone to metastasis and has the poorest prognosis. Over 75% of ARMS tumors possess a t(2;13)(q35;q14), or the variant t(1;13)(p36;q14) chromosomal translocation which generates a PAX3-FOXO1a or PAX7-FOXO1a fusion protein, respectively. Using murine primary myoblasts (a likely cell of origin for rhabdomyosarcoma), PAX3 and PAX3-FKHR were ectopically expressed and microarray analysis was performed to identify differentially regulated genes. Several genes were identified and two genes, Cannabinoid Receptor 1 (Cnr1/Cb1) and the pro-apoptotic BH3-only protein Noxa (Pmaip1), were chosen for further study. In primary myoblasts, Cnr1 is required but not sufficient to enhance the invasive capacity of PAX3-FOXO1a expressing primary myoblasts. This appears to be mediated through Cnr1 constitutive activity. In vivo the Cnr1 inverse agonist AM251 prevents lung metastasis formation in immunocompromized mice. This implicates Cnr1 as a potential therapeutic target to inhibit the metastatic capacity of ARMS tumors. Noxa expression is increased in PAX3-FOXO1a expressing primary myoblasts in a p53-independent manner. Moreover, PAX3-FOXO1a expression, through the up regulation of Noxa, increases the sensitivity of primary myoblasts to bortezomib and GSI-1, which also induce apoptosis in a p53-independent, Noxa-dependent manner. In addition, the up regulation of Noxa increases cell sensitivity to the anti-apoptotic Bcl-2 family inhibitor ABT-737. Bortezomib treatment in vivo significantly inhibits the growth of subcutaneous ARMS model tumors and prolongs the survival of treated animals. 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 232.