Abstract A67: Canonical WNT/β;-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal

Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress TPC function, a large-scale chemical screen comprising of ∼40,000 compounds including 47% FDA-approved drugs was completed, identifying GSK3-inhibitors as potent suppressors of ERMS growth through inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT pathway, recombinant WNT3A and a stabilized β-catenin enhanced differentiation and reduced self-renewal in human ERMS cell lines. Moreover, treatment of tumor-bearing zebrafish with a GSK3 inhibitor activated the WNT/β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. As canonical WNT signaling is essential for transition from muscle stem cell proliferation to myogenic differentiation during regeneration, our findings suggest that the same developmental pathways that regulate muscle stem cell self-renewal also contribute to tumorigenesis in ERMS. GSK3 inhibitors are being assessed for their efficacy in inhibiting growth as well as inducing differentiation of human ERMS in xenograft mouse models. Our work has identified the vital role of canonical WNT pathway in regulating differentiation and self-renewal of ERMS and demonstrated the effective application of small molecule inhibitors to target differentiation of TPCs in ERMS. Citation Format: Eleanor Chen, Michael DeRan, Katherine Brooke Grandinetti, Myron Ignatius, Ryan Clagg, Karin McCarthy, Riadh Lobbardi, Xu Wu, David Langenau. Canonical WNT/β;-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal. [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 A67.