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@ARTICLE{Mller:170569,
      author       = {M. Müller$^*$ and L. Rösch$^*$ and S. Najafi$^*$ and C.
                      Gatzweiler$^*$ and J. Ridinger$^*$ and X. F. Gerloff$^*$ and
                      D. T. W. Jones$^*$ and J. Baßler and S. Kreth$^*$ and S.
                      Stainczyk$^*$ and K. Frese and B. Meder and F.
                      Westermann$^*$ and T. Milde$^*$ and H. Peterziel$^*$ and O.
                      Witt$^*$ and I. Oehme$^*$},
      title        = {{C}ombining {APR}-246 and {HDAC}-{I}nhibitors: {A} {N}ovel
                      {T}argeted {T}reatment {O}ption for {N}euroblastoma.},
      journal      = {Cancers},
      volume       = {13},
      number       = {17},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2021-02020},
      pages        = {4476},
      year         = {2021},
      note         = {#EA:B310#LA:B310#},
      abstract     = {APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent
                      anti-cancer drug in clinical trials and was initially
                      developed as a p53 refolding agent. As an alternative mode
                      of action, the elevation of reactive oxygen species (ROS)
                      has been proposed. Through an in silico analysis, we
                      investigated the responses of approximately 800 cancer cell
                      lines (50 entities; Cancer Therapeutics Response Portal,
                      CTRP) to APR-246 treatment. In particular, neuroblastoma,
                      lymphoma and acute lymphocytic leukemia cells were highly
                      responsive. With gene expression data from the Cancer Cell
                      Line Encyclopedia (CCLE; n = 883) and patient samples (n =
                      1643) from the INFORM registry study, we confirmed that
                      these entities express low levels of SLC7A11, a previously
                      described predictive biomarker for APR-246 responsiveness.
                      Combining the CTRP drug response data with the respective
                      CCLE gene expression profiles, we defined a novel gene
                      signature, predicting the effectiveness of APR-246 treatment
                      with a sensitivity of $90\%$ and a specificity of $94\%.$ We
                      confirmed the predicted APR-246 sensitivity in 8/10 cell
                      lines and in ex vivo cultures of patient samples. Moreover,
                      the combination of ROS detoxification-impeding APR-246 with
                      approved HDAC-inhibitors, known to elevate ROS,
                      substantially increased APR-246 sensitivity in cell cultures
                      and in vivo in two zebrafish neuroblastoma xenograft models.
                      These data provide evidence that APR-246, in combination
                      with HDAC-inhibitors, displays a novel potent targeted
                      treatment option for neuroblastoma patients.},
      keywords     = {ROS (Other) / TP53 (Other) / histone deacetylases (Other) /
                      pediatric tumors of the nervous system (Other) / precision
                      medicine (Other) / response prediction biomarker (Other) /
                      small molecule inhibitors (Other)},
      cin          = {B310 / B360 / HD01 / B087},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)B087-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34503286},
      doi          = {10.3390/cancers13174476},
      url          = {https://inrepo02.dkfz.de/record/170569},
}