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@ARTICLE{Keller:178319,
      author       = {K. M. Keller and S. Krausert$^*$ and A. Gopisetty$^*$ and
                      D. Luedtke and J. Koster and N. A. Schubert and A.
                      Rodríguez and S. R. van Hooff and D. Stichel$^*$ and M. E.
                      M. Dolman and G. Vassal and S. M. Pfister$^*$ and H. N.
                      Caron and L. F. Stancato and J. J. Molenaar and N.
                      Jäger$^*$ and M. Kool$^*$},
      title        = {{T}arget {A}ctionability {R}eview: a systematic evaluation
                      of replication stress as a therapeutic target for paediatric
                      solid malignancies.},
      journal      = {European journal of cancer},
      volume       = {162},
      issn         = {0014-2964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2021-03266},
      pages        = {107 - 117},
      year         = {2022},
      note         = {#EA:B062#LA:B062#},
      abstract     = {Owing to the high numbers of paediatric cancer-related
                      deaths, advances in therapeutic options for childhood cancer
                      is a heavily studied field, especially over the past decade.
                      Classical chemotherapy offers some therapeutic benefit but
                      has proven long-term complications in survivors, and there
                      is an urgent need to identify novel target-driven therapies.
                      Replication stress is a major cause of genomic instability
                      in cancer, triggering the stalling of the replication fork.
                      Failure of molecular response by DNA damage checkpoints, DNA
                      repair mechanisms and restarting the replication forks can
                      exacerbate replication stress and initiate cell death
                      pathways, thus presenting as a novel therapeutic target. To
                      bridge the gap between preclinical evidence and clinical
                      utility thereof, we apply the literature-driven systematic
                      target actionability review methodology to published
                      proof-of-concept (PoC) data related to the process of
                      replication stress.A meticulous PubMed literature search was
                      performed to gather replication stress-related articles
                      (published between 2014 and 2021) across 16 different
                      paediatric solid tumour types. Articles that fulfilled
                      inclusion criteria were uploaded into the R2 informatics
                      platform [r2.amc.nl] and assessed by critical appraisal. Key
                      evidence based on nine pre-established PoC modules was
                      summarised, and scores based on the quality and outcome of
                      each study were assigned by two separate reviewers. Articles
                      with discordant modules/scores were re-scored by a third
                      independent reviewer, and a final consensus score was agreed
                      upon by adjudication between all three reviewers. To
                      visualise the final scores, an interactive heatmap
                      summarising the evidence and scores associated with each PoC
                      module across all, including paediatric tumour types, were
                      generated.145 publications related to targeting replication
                      stress in paediatric tumours were systematically reviewed
                      with an emphasis on DNA repair pathways and cell cycle
                      checkpoint control. Although various targets in these
                      pathways have been studied in these diseases to different
                      extents, the results of this extensive literature search
                      show that ATR, CHK1, PARP or WEE1 are the most promising
                      targets using either single agents or in combination with
                      chemotherapy or radiotherapy in neuroblastoma, osteosarcoma,
                      high-grade glioma or medulloblastoma. Targeting these
                      pathways in other paediatric malignancies may work as well,
                      but here, the evidence was more limited. The evidence for
                      other targets (such as ATM and DNA-PK) was also limited but
                      showed promising results in some malignancies and requires
                      more studies in other tumour types. Overall, we have created
                      an extensive overview of targeting replication stress across
                      16 paediatric tumour types, which can be explored using the
                      interactive heatmap on the R2 target actionability review
                      platform
                      $[https://hgserver1.amc.nl/cgi-bin/r2/main.cgi?option=imi2_targetmap_v1].$},
      subtyp        = {Review Article},
      keywords     = {Cell cycle checkpoints (Other) / DNA repair (Other) /
                      Paediatric oncology (Other) / Preclinical research (Other) /
                      Replication stress (Other) / Systematic review (Other) /
                      Targeted drugs (Other)},
      cin          = {B062 / HD01 / B300},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B300-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34963094},
      doi          = {10.1016/j.ejca.2021.11.030},
      url          = {https://inrepo02.dkfz.de/record/178319},
}