Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in Atypical Teratoid/Rhabdoid Tumors

BackgroundAtypical Teratoid/Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Despite recent advances in understanding the molecular characteristics and subclasses of these tumors, effective therapeutic options remain scarce. MethodsIn this study, we developed and validated a novel patient-derived ATRT culture and xenograft model, which we used alongside a panel of other primary ATRT models for large-scale drug discovery assays. The identified hits were mechanistically and therapeutically investigated using an array of molecular assays and two orthotopic xenograft murine models. ResultsWe found that ATRT are selectively sensitive to the nucleoside analogue gemcitabine, with additional efficacy in Sonic Hedgehog (SHH)-subtype ATRT. Gene expression profiles and protein analyses indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), resulting in cell death through activation of NF-kB and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the SHH signaling activator GLI2, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival (p<0.005, log-rank test) and yielded long-term survivors in two independent patient-derived xenograft models. ConclusionsThese findings demonstrate that ATRT are highly sensitive to gemcitabine treatment, and we propose that gemcitabine may form part of a future multimodal treatment strategy for ATRT. Key points- ATRT are specifically sensitive to gemcitabine treatment - SIRT1 may serve as a novel therapeutic target in ATRT - Gemcitabine should be considered for clinical use in ATRT patients Importance of the studyAtypical Teratoid/Rhabdoid Tumors (ATRT) are highly malignant pediatric brain tumors with a 5-year survival of merely 30%, for which effective treatment options are limited. In this study, we propose a potential novel treatment strategy for ATRT patients. We show that ATRT are highly sensitive to the chemotherapeutic gemcitabine, that takes advantage of ATRT-specific SIRT1 overexpression and disrupts p53 suppression and hedgehog signaling. Importantly, we show that gemcitabine significantly prolongs survival of ATRT patient-derived xenograft models, prolonging survival by over 30%. This effect was achieved using gemcitabine concentrations that are achievable in human brain and well-tolerated in pediatric patients. As such, gemcitabine could be readily incorporated into clinical treatment protocols and expand the still very limited therapeutic options for ATRT-patients.