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@ARTICLE{Simovic:169016,
      author       = {M. Simovic$^*$ and M. Bolkestein$^*$ and M. Moustafa$^*$
                      and J. K. L. Wong$^*$ and V. Körber$^*$ and S.
                      Benedetto$^*$ and U. Khalid$^*$ and H. S. Schreiber$^*$ and
                      M. Jugold$^*$ and A. Korshunov$^*$ and D. Hübschmann$^*$
                      and N. Mack$^*$ and S. Brons and P.-C. Wei$^*$ and M. O.
                      Breckwoldt and S. Heiland and M. Bendszus and D. Jürgen$^*$
                      and T. Höfer$^*$ and M. Zapatka$^*$ and M. Kool$^*$ and S.
                      M. Pfister$^*$ and A. Abdollahi$^*$ and A. Ernst$^*$},
      title        = {{C}arbon ion radiotherapy eradicates medulloblastomas with
                      chromothripsis in an orthotopic {L}i-{F}raumeni
                      patient-derived mouse model.},
      journal      = {Neuro-Oncology},
      volume       = {23},
      number       = {12},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2021-01184},
      pages        = {2028-2041},
      year         = {2021},
      note         = {#EA:B420#LA:B420# / 2021 Dec 1;23(12):2028-2041},
      abstract     = {Medulloblastomas 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.},
      keywords     = {PARP inhibitor (Other) / carbon ion radiotherapy (Other) /
                      chromothripsis (Other) / medulloblastoma (Other) / synthetic
                      lethality (Other)},
      cin          = {B420 / HD01 / B060 / B086 / W240 / B300 / B062 / B400 /
                      E050 / E210},
      ddc          = {610},
      cid          = {I:(DE-He78)B420-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B060-20160331 / I:(DE-He78)B086-20160331 /
                      I:(DE-He78)W240-20160331 / I:(DE-He78)B300-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B400-20160331 /
                      I:(DE-He78)E050-20160331 / I:(DE-He78)E210-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34049392},
      doi          = {10.1093/neuonc/noab127},
      url          = {https://inrepo02.dkfz.de/record/169016},
}