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@ARTICLE{Schfer:291420,
      author       = {T. Schäfer$^*$ and L. I. Knol and F. V. Haas and A.
                      Hartley$^*$ and S. Pernickel$^*$ and A. Jády and M. S. C.
                      Finkbeiner and J. Achberger and S. Arelaki$^*$ and Z.
                      Modic$^*$ and K. Schröer and W. Zhang and B. Schmidt and P.
                      Schuster and S. Haferkamp and J. Doerner and F. Gebauer and
                      M. Ackermann and H.-M. Kvasnicka and A. Kulkarni and S. T.
                      F. Bots and V. Kemp and L. J. A. C. Hawinkels and A. R.
                      Poetsch and R. C. Hoeben and A. Ehrhardt and A. Marchini$^*$
                      and C. Ball$^*$ and C. Engeland$^*$ and G. Ungerechts$^*$},
      title        = {{B}iomarker screen for efficacy of oncolytic virotherapy in
                      patient-derived pancreatic cancer cultures.},
      journal      = {EBioMedicine},
      volume       = {105},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2024-01394},
      pages        = {105219},
      year         = {2024},
      note         = {#EA:D490#LA:D490#},
      abstract     = {Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity
                      with unmet medical need. To assess the therapeutic potential
                      of oncolytic virotherapy (OVT) against PDAC, different
                      oncolytic viruses (OVs) are currently investigated in
                      clinical trials. However, systematic comparisons of these
                      different OVs in terms of efficacy against PDAC and
                      biomarkers predicting therapeutic response are lacking.We
                      screened fourteen patient-derived PDAC cultures which
                      reflect the intra- and intertumoural heterogeneity of PDAC
                      for their sensitivity to five clinically relevant OVs,
                      namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC,
                      measles vaccine strain MV-NIS, reovirus jin-3, and
                      protoparvovirus H-1PV. Live cell analysis, quantification of
                      viral genome/gene expression, cell viability as well as
                      cytotoxicity assays and titration of viral progeny were
                      conducted. Transcriptome profiling was employed to identify
                      potential predictive biomarkers for response to OV
                      treatment.Patient-derived PDAC cultures showed individual
                      response patterns to OV treatment. Twelve of fourteen
                      cultures were responsive to at least one OV, with no single
                      OV proving superior or inferior across all cultures. Known
                      host factors for distinct viruses were retrieved as
                      potential biomarkers. Compared to the classical molecular
                      subtype, the quasi-mesenchymal or basal-like subtype of PDAC
                      was found to be more sensitive to H-1PV, jin-3, and T-VEC.
                      Generally, expression of viral entry receptors did not
                      correlate with sensitivity to OV treatment, with one
                      exception: Expression of Galectin-1 (LGALS1), a factor
                      involved in H-1PV entry, positively correlated with H-1PV
                      induced cell killing. Rather, cellular pathways controlling
                      immunological, metabolic and proliferative signaling
                      appeared to determine outcome. For instance, high baseline
                      expression of interferon-stimulated genes (ISGs) correlated
                      with relative resistance to oncolytic measles virus, whereas
                      low cyclic GMP-AMP synthase (cGAS) expression was associated
                      with exceptional response. Combination treatment of MV-NIS
                      with a cGAS inhibitor improved tumour cell killing in
                      several PDAC cultures and cells overexpressing cGAS were
                      found to be less sensitive to MV oncolysis.Considering the
                      heterogeneity of PDAC and the complexity of biological
                      therapies such as OVs, no single biomarker can explain the
                      spectrum of response patterns. For selection of a particular
                      OV, PDAC molecular subtype, ISG expression as well as
                      activation of distinct signaling and metabolic pathways
                      should be considered. Combination therapies can overcome
                      resistance in specific constellations. Overall, oncolytic
                      virotherapy is a viable treatment option for PDAC, which
                      warrants further development. This study highlights the need
                      for personalised treatment in OVT. By providing all primary
                      data, this study provides a rich source and guidance for
                      ongoing developments.German National Science Foundation
                      (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid
                      (Deutsche Krebshilfe), German National Academic Scholarship
                      Foundation (Studienstiftung des deutschen Volkes), Survival
                      with Pancreatic Cancer Foundation.},
      keywords     = {Cancer immunotherapy (Other) / Oncolytic virotherapy
                      (Other) / Pancreatic cancer (Other) / Viral vectors (Other)},
      cin          = {D490 / D420 / B280 / DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)D490-20160331 / I:(DE-He78)D420-20160331 /
                      I:(DE-He78)B280-20160331 / I:(DE-He78)DD01-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38941955},
      doi          = {10.1016/j.ebiom.2024.105219},
      url          = {https://inrepo02.dkfz.de/record/291420},
}