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@ARTICLE{Endersby:167180,
      author       = {R. Endersby and J. Whitehouse and A. Pribnow and M.
                      Kuchibhotla and H. Hii and B. Carline and S. Gande and J.
                      Stripay and M. Ancliffe and M. Howlett and T. Schoep and C.
                      George and C. Andradas and P. Dyer and M. Schluck and B.
                      Patterson and S. K. Tacheva-Gigorova and M. N. Cooper and G.
                      Robinson and C. Stewart and S. M. Pfister$^*$ and M.
                      Kool$^*$ and T. Milde$^*$ and A. Gajjar and T. Johns and R.
                      J. Wechsler-Reya and M. F. Roussel and N. G. Gottardo},
      title        = {{S}mall-molecule screen reveals synergy of cell cycle
                      checkpoint kinase inhibitors with {DNA}-damaging
                      chemotherapies in medulloblastoma.},
      journal      = {Science translational medicine},
      volume       = {13},
      number       = {577},
      issn         = {1946-6242},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DKFZ-2021-00171},
      pages        = {eaba7401 -},
      year         = {2021},
      abstract     = {Medulloblastoma (MB) consists of four core molecular
                      subgroups with distinct clinical features and prognoses.
                      Treatment consists of surgery, followed by radiotherapy and
                      cytotoxic chemotherapy. Despite this intensive approach,
                      outcome remains dismal for patients with certain subtypes of
                      MB, namely, MYC-amplified Group 3 and TP53-mutated SHH.
                      Using high-throughput assays, six human MB cell lines were
                      screened against a library of 3208 unique compounds. We
                      identified 45 effective compounds from the screen and found
                      that cell cycle checkpoint kinase (CHK1/2) inhibition
                      synergistically enhanced the cytotoxic activity of
                      clinically used chemotherapeutics cyclophosphamide,
                      cisplatin, and gemcitabine. To identify the best-in-class
                      inhibitor, multiple CHK1/2 inhibitors were assessed in mice
                      bearing intracranial MB. When combined with DNA-damaging
                      chemotherapeutics, CHK1/2 inhibition reduced tumor burden
                      and increased survival of animals with high-risk MB, across
                      multiple different models. In total, we tested 14 different
                      models, representing distinct MB subgroups, and data were
                      validated in three independent laboratories.
                      Pharmacodynamics studies confirmed central nervous system
                      penetration. In mice, combination treatment significantly
                      increased DNA damage and apoptosis compared to chemotherapy
                      alone, and studies with cultured cells showed that CHK
                      inhibition disrupted chemotherapy-induced cell cycle arrest.
                      Our findings indicated CHK1/2 inhibition, specifically with
                      LY2606368 (prexasertib), has strong chemosensitizing
                      activity in MB that warrants further clinical investigation.
                      Moreover, these data demonstrated that we developed a robust
                      and collaborative preclinical assessment platform that can
                      be used to identify potentially effective new therapies for
                      clinical evaluation for pediatric MB.},
      cin          = {B062},
      ddc          = {500},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33472956},
      doi          = {10.1126/scitranslmed.aba7401},
      url          = {https://inrepo02.dkfz.de/record/167180},
}