Abstract 3450: Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors

Abstract

Abstract Peripheral sympathetic nervous system tumors are the most common extra-cranial pediatric tumors in children and include neuroblastoma, ganglioneuroblastoma (intermixed and nodular) and ganglioneuroma. The etiology and molecular pathogenesis of ganglioneuromas remains largely unknown. Surgery is the only effective therapy for ganglioneuroma, which can be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is need for well tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma, and therefore limit surgical morbidity. Here we found high levels of phosphorylated AKT expressed in 10 of 11 patients with ganglioneuroma, but only in 1 of 15 who had poorly differentiated neuroblastoma (p<0.0001, Fisher's exact test). Consistent with these results, zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Histopathological analysis and whole-transcriptome sequencing revealed that zebrafish ganglioneuroma highly resembles human ganglioneuroma. Inhibition of the downstream AKT target, mTOR, using sirolimus in zebrafish with ganglioneuroma effectively reduced the tumor burden, providing preclinical evidence for efficacy with this well tolerated drug. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of sirolimus as a means to shrink large ganglioneuromas prior to resection in order to reduce surgical morbidity. Citation Format: Ting Tao, Hui Shi, Adam D. Durbin, Meng Wang, Antonio R. Perez-Atayde, Wendy B. London, Alejandro Gutierrez, Bernardo Lemos, A. Thomas Look. Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3450.