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@ARTICLE{Haller:305574,
      author       = {B. Haller and G. H. S. Richter$^*$ and M. Wachtel and L.
                      Schuler and C. Regina and B. Renz and M. Jens$^*$ and I.
                      Bechtold and Y. Gadasheva and E. Hamed and S. Kisele and M.
                      Knoblauch and M. R. Koch and D. Lupar$^*$ and S. Nakano and
                      K. Pardon$^*$ and P. J. Pärschke$^*$ and C. Winter$^*$ and
                      U. Tölch and B. W. Schäfer and A. Banito$^*$ and I. von
                      Lüttichau and S. Hettmer},
      title        = {{EPICYCLE}: {A} confirmatory preclinical study of the
                      anti-rhabdomyosarcoma efficacy of {BET} bromodomain and
                      cyclin-dependent kinase 9 inhibitors.},
      journal      = {Biomedicine $\&$ pharmacotherapy},
      volume       = {192},
      issn         = {0300-0893},
      address      = {Paris [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-02236},
      pages        = {118704},
      year         = {2025},
      note         = {ISSN 0753-3322},
      abstract     = {Hypothesis-driven academic research identifies
                      interventions with likely disease-specific effects. Yet,
                      many candidate drugs fail upon further development,
                      emphasizing the need for acquisition of more robust
                      preclinical data. We demonstrate that planning and executing
                      multicentre confirmatory preclinical studies in an academic
                      setting by applying the quality standards of early phase
                      clinical trials is feasible. Randomization, blinding,
                      stratification by sex of and quality control measures were
                      carried out successfully. The primary objective of our
                      specific study - to confirm synergistic effects of BET
                      bromodomain protein 4 (BRD4) and cyclin-dependent kinase 9
                      (CDK9) inhibitors against PAX3::FOXO1 (P3F)-positive
                      rhabdomyosarcoma (RMS) - was not met. Post-hoc analyses
                      support that single-agent BRD4 inhibition by JQ1 effectively
                      reduced the growth and viability of P3F+ RMS cells ex vivo
                      with adequate on-target activity as evidenced by reduced
                      expression of P3F, MYCN, MYOG, and MYOD. The
                      antiproliferative effects of JQ1 and vincristine were
                      comparable, and there was trend towards reduced and delayed
                      xenograft growth in JQ1-treated mice. Yet, in vivo assays
                      were flawed by lower xenograft penetrance, variable
                      xenograft latency, gastrointestinal toxicity, and inadequate
                      on-target activity of drugs. We conclude that confirmatory
                      preclinical trials allow for robust assessment of the
                      efficacy of candidate interventions and reduce bias in
                      academic research. The study platform established here
                      provides a framework that may be of particular benefit for
                      the development of new drugs for rare cancers.},
      keywords     = {BRD4 (Other) / CDK9 (Other) / Confirmatory preclinical
                      study (Other) / Rhabdomyosarcoma (Other) / Synergism
                      (Other)},
      cin          = {BE01 / B380},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331 / I:(DE-He78)B380-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41161003},
      doi          = {10.1016/j.biopha.2025.118704},
      url          = {https://inrepo02.dkfz.de/record/305574},
}