Abstract B48: The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some anti-tumor efficacy in RMS cells in vitro, however the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (known as ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable in vivo micromolar concentrations. ST1926 induced an early DNA damage response, which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion protein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in retarding the growth of ARMS and ERMS xenografts, and induced a prominent DNA damage response. We conclude that ST1926 has preclinical efficacy against RMS, and should be considered further investigated in clinical trials, possibly in combination therapy. Citation Format: Hussein Basma, Sandra Ghayad, Angelo Mancinelli, Claudio Pisano, Nadine Darwiche, Raya Saab. The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B48.