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@ARTICLE{Schubert:180249,
      author       = {N. A. Schubert and C. Y. Chen and A. Rodríguez and J.
                      Koster and M. Dowless and S. M. Pfister$^*$ and D. J.
                      Shields and L. F. Stancato and G. Vassal and H. N. Caron and
                      M. L. van den Boogaard and A. G. Henssen$^*$ and J. J.
                      Molenaar},
      title        = {{T}arget actionability review to evaluate {CDK}4/6 as a
                      therapeutic target in paediatric solid and brain tumours.},
      journal      = {European journal of cancer},
      volume       = {170},
      issn         = {0014-2964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2022-01200},
      pages        = {196 - 208},
      year         = {2022},
      abstract     = {Childhood cancer is still a leading cause of death around
                      the world. To improve outcomes, there is an urgent need for
                      tailored treatment. The systematic evaluation of existing
                      preclinical data can provide an overview of what is known
                      and identify gaps in the current knowledge. Here, we applied
                      the target actionability review (TAR) methodology to assess
                      the strength and weaknesses of available scientific
                      literature on CDK4/6 as a therapeutic target in paediatric
                      solid and brain tumours by structured critical
                      appraisal.Using relevant search terms in PubMed, a list of
                      original publications investigating CDK4/6 in paediatric
                      solid tumour types was identified based on relevancy
                      criteria. Each publication was annotated for the tumour type
                      and categorised into separate proof-of-concept (PoC) data
                      modules. Based on rubrics, quality and experimental outcomes
                      were scored independently by two reviewers. A third reviewer
                      evaluated and adjudicated score discrepancies. Scores for
                      each PoC module were averaged for each tumour type and
                      visualised in a heatmap matrix in the publicly available R2
                      data portal.This CDK4/6 TAR, generated by analysis of 151
                      data entries from 71 publications, showed frequent genomic
                      aberrations of CDK4/6 in rhabdomyosarcoma, osteosarcoma,
                      high-grade glioma, medulloblastoma, and neuroblastoma.
                      However, a clear correlation between CDK4/6 aberrations and
                      compound efficacy is not coming forth from the literature.
                      Our analysis indicates that several paediatric indications
                      would need (further) preclinical evaluation to allow for
                      better recommendations, especially regarding the dependence
                      of tumours on CDK4/6, predictive biomarkers, resistance
                      mechanisms, and combination strategies. Nevertheless, our
                      TAR heatmap provides support for the relevance of CDK4/6
                      inhibition in Ewing sarcoma, medulloblastoma, malignant
                      peripheral nerve sheath tumour and to a lesser extent
                      neuroblastoma, rhabdomyosarcoma, rhabdoid tumour and
                      high-grade glioma. The interactive heatmap is accessible
                      through R2 $[r2platform.com/TAR/CDK4_6].$},
      keywords     = {CDK4/6 (Other) / Cell cycle inhibitors (Other) / Paediatric
                      oncology (Other) / Preclinical research (Other) / Systematic
                      review (Other) / Targeted therapy (Other)},
      cin          = {B062 / HD01 / BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)BE01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35671543},
      doi          = {10.1016/j.ejca.2022.04.028},
      url          = {https://inrepo02.dkfz.de/record/180249},
}