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000169016 1001_ $$0P:(DE-He78)1fdaffee272e57a73f861a0ea36c4079$$aSimovic, Milena$$b0$$eFirst author$$udkfz
000169016 245__ $$aCarbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model.
000169016 260__ $$aOxford$$bOxford Univ. Press$$c2021
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000169016 520__ $$aMedulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy.We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological (MRI), cellular (markers of neurogenesis and DNA damage-repair) and molecular characterization (whole-genome sequencing).In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days post-irradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the post-radiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, p<0.0001). No major change in the clonal composition was detected in the relapsed model.The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Post-radiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.
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000169016 650_7 $$2Other$$aPARP inhibitor
000169016 650_7 $$2Other$$acarbon ion radiotherapy
000169016 650_7 $$2Other$$achromothripsis
000169016 650_7 $$2Other$$amedulloblastoma
000169016 650_7 $$2Other$$asynthetic lethality
000169016 7001_ $$0P:(DE-He78)2f672b5ff4fc0d5ba62362e2be763b33$$aBolkestein, Michiel$$b1
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000169016 7001_ $$0P:(DE-HGF)0$$aWong, John K L$$b3
000169016 7001_ $$0P:(DE-He78)467f2d039931bfae1a497c4a6c54804c$$aKörber, Verena$$b4$$udkfz
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000169016 7001_ $$0P:(DE-He78)a1d9ea75dd03dbe8e7cd31adc141d10d$$aSchreiber, Hannah Sophia$$b7$$udkfz
000169016 7001_ $$0P:(DE-He78)f12dec7b80065347181cf69f8233b40d$$aJugold, Manfred$$b8$$udkfz
000169016 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b9$$udkfz
000169016 7001_ $$0P:(DE-He78)a5218e4871866cd5ab2312e594ca403d$$aHübschmann, Daniel$$b10$$udkfz
000169016 7001_ $$0P:(DE-He78)e73a0a4fab40344d89d693cbe1df3109$$aMack, Norman$$b11$$udkfz
000169016 7001_ $$00000-0002-4695-0816$$aBrons, Stephan$$b12
000169016 7001_ $$0P:(DE-He78)56a961d57d7839fc2d2ebb60c575d9c4$$aWei, Pei-Chi$$b13$$udkfz
000169016 7001_ $$aBreckwoldt, Michael O$$b14
000169016 7001_ $$aHeiland, Sabine$$b15
000169016 7001_ $$aBendszus, Martin$$b16
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