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@ARTICLE{An:292513,
      author       = {J. An and R. Kurilov$^*$ and T. Peccerella and F. Bergmann
                      and M. Edderkaoui and A. Lim and X. Zhou and K. Pfütze$^*$
                      and A. Schulz$^*$ and S. Wolf$^*$ and K. Hu and C.
                      Springfeld and S. S. Mughal$^*$ and L. Zezlina$^*$ and F.
                      Fortunato and G. Beyer and J. Mayerle and S. Roth and J.
                      Hulkkonen and D. Merz and S. Ei and A. Mehrabi and M. Loos
                      and M. Al-Saeedi and C. W. Michalski and M. W. Büchler and
                      T. Hackert and B. Brors$^*$ and S. J. Pandol and P.
                      Bailey$^*$ and J. P. Neoptolemos},
      title        = {{M}etavert synergises with standard cytotoxics in human
                      {PDAC} organoids and is associated with transcriptomic
                      signatures of therapeutic response.},
      journal      = {Translational oncology},
      volume       = {49},
      issn         = {1944-7124},
      address      = {Ann Arbor, Mich.},
      publisher    = {[Verlag nicht ermittelbar]},
      reportid     = {DKFZ-2024-01759},
      pages        = {102109},
      year         = {2024},
      note         = {#EA:B330#LA:B330# / Sample Processing Laborator Pfütze},
      abstract     = {Despite some recent advances, pancreatic ductal
                      adenocarcinoma (PDAC) remains a growing oncological
                      challenge. New drugs capable of targeting more than one
                      oncogenic pathway may be one way to improve patient
                      outcomes. This study characterizes the effectiveness of
                      Metavert a first-in-class dual inhibitor of GSK3-β and
                      histone deacetylase in treating PDAC as a single agent or in
                      combination with standard cytotoxics.Thirty-six
                      Patient-Derived Organoids (hPDOs) characterised by RNASeq
                      and whole exome sequencing were treated with Metavert alone
                      or in combination with standard cytotoxics. Transcriptomic
                      signatures (TS) representing sensitivity to Metavert alone
                      or sensitivity to Metavert + irinotecan (IR) were evaluated
                      in 47 patient samples, chemo-naïve in 26 and
                      post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14,
                      both=2) with companion multiplexed immunofluorescence and
                      RNASeq data.Metavert combined with gemcitabine, irinotecan,
                      5FU, oxaliplatin, and paclitaxel was synergistic in the
                      hPDOs. Basal-subtype hPDOs were more sensitive to Metavert
                      alone whereas the Metavert+IR combination exhibited synergy
                      in Classical-subtype hPDOs with increased apoptosis and
                      autophagy. hPDO-derived TS evaluated in PDAC tissues
                      demonstrated that Metavert-TSHi samples were enriched for
                      mRNA splicing and DNA repair processes; they were associated
                      with Basal-like tissues but also with GATA6+ve-chemo-naïve
                      samples and were higher following gemcitabine but not
                      FOLFIRINOX treatment. In contrast, Metavert+IR-TSHI samples
                      were enriched for TP53 pathways; they were associated with
                      Classical-like pretreatment samples and with
                      GATA6+ve/KRT17+ve hybrid cell types following FOLFIRINOX,
                      but not gemcitabine treatment, and were unrelated to
                      transcriptional subtypes.Metavert as a single agent and in
                      combination with irinotecan offers novel strategies for
                      treating pancreatic cancer.},
      keywords     = {Apoptosis (Other) / Autophagy (Other) / GSK3-β (Other) /
                      Histone deacetylases (Other) / Molecular subtypes (Other) /
                      Pancreatic cancer (Other)},
      cin          = {B330 / W190 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B330-20160331 / I:(DE-He78)W190-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39217851},
      doi          = {10.1016/j.tranon.2024.102109},
      url          = {https://inrepo02.dkfz.de/record/292513},
}