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000292537 1001_ $$aMetselaar, Dennis S$$b0
000292537 245__ $$aGemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.
000292537 260__ $$aMaryland Heights, MO$$bElsevier$$c2024
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000292537 520__ $$aAtypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.
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000292537 650_7 $$2Other$$aATRT
000292537 650_7 $$2Other$$aatypical teratoid/rhabdoid tumor
000292537 650_7 $$2Other$$agemcitabine
000292537 650_7 $$2Other$$aneuro oncology
000292537 650_7 $$2Other$$ap53
000292537 650_7 $$2Other$$apatient-derived models
000292537 650_7 $$2Other$$apediatric oncology
000292537 650_7 $$2Other$$asirtuin 1
000292537 650_7 $$2Other$$atherapy development
000292537 7001_ $$aMeel, Michaël H$$b1
000292537 7001_ $$aGoulding, Joshua R$$b2
000292537 7001_ $$adu Chatinier, Aimeé$$b3
000292537 7001_ $$aRigamonti, Leyla$$b4
000292537 7001_ $$aWaranecki, Piotr$$b5
000292537 7001_ $$0P:(DE-He78)45dfe5449533ea8aff20e193dee5973a$$aGeisemeyer, Neal$$b6$$udkfz
000292537 7001_ $$ade Gooijer, Mark C$$b7
000292537 7001_ $$aBreur, Marjolein$$b8
000292537 7001_ $$aKoster, Jan$$b9
000292537 7001_ $$aVeldhuijzen van Zanten, Sophie E M$$b10
000292537 7001_ $$aBugiani, Marianna$$b11
000292537 7001_ $$aFranke, Niels E$$b12
000292537 7001_ $$aReddy, Alyssa$$b13
000292537 7001_ $$aWesseling, Pieter$$b14
000292537 7001_ $$aKaspers, Gertjan J L$$b15
000292537 7001_ $$aHulleman, Esther$$b16
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