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@INPROCEEDINGS{Oswald:294423,
      author       = {E. Oswald and D. Lenhard and K. Lashuk and S. Pfister$^*$
                      and L. Stancato and J. Schueler},
      title        = {{A}bstract 3524: {P}harmacological characterization of
                      pediatric brain tumor {PDX} models in a single mouse trial
                      format},
      issn         = {1538-7445},
      reportid     = {DKFZ-2024-02252},
      year         = {2023},
      abstract     = {Cancer remains the leading cause of disease-related death
                      in children. Preclinical drug testing to identify promising
                      treatment options for relapsed patients or those with poor
                      prognosis is hindered by the lack of well characterized and
                      annotated preclinical models. In the framework of the ITCCP4
                      consortium (www.ITCCP4.eu) our group determined the
                      pharmacological profile of 47 orthotopically implanted
                      pediatric brain PDX models. The panel comprised 21 high
                      grade glioma (HGG), 13 medulloblastoma (MB), eight
                      ependymoma (EP), three non-classified brain tumors (XT), one
                      atypical teratoid/rhabdoid tumor (AT/RT) and one
                      neuroblastoma (NB).. Depending on the tumor type the models
                      were screened in an eleven or twelve arms single mouse trial
                      study layout. Three treatment arms comprised standard of
                      care cytotoxic compounds and radiation, whereas the other
                      arms covered targeted therapies, mostly small molecules.
                      Tumor load was determined using a fluorescent based in vivo
                      imaging technology based on the lentiviral transient
                      transduction of the PDX cells with iRFP713 prior to
                      implantation into the brain. In addition, body weight and
                      neurological scoring was applied to determine the overall
                      condition of the animals. At the end of the study brain
                      tissue was harvested and tumor load confirmed by
                      immunohistochemistry. The mean overall survival of the
                      orthotopic implanted animals on study was 48 days with a
                      minimum of 7 days and a maximum of 132 days. Overall, the
                      treatment was well tolerated in the tumor bearing animals as
                      determined by body weight measurement. However, the
                      combination of two cytotoxic drugs in some of the arms
                      needed dose adjustments due to increased toxicity. Across
                      all tumor types at least one of the cytotoxic arms improved
                      overall survival of the tumor bearing animals markedly:
                      Temozolomide and Lomustine for HGG (43d and 50d,
                      respectively vs 28d in the control arm), Lomustine and
                      Endoxan for MB (99d and 73d, respectively vs 61d in the
                      control arm), and Actinomycin D for EP (64d vs 52d).
                      However, several of the targeted agents showed a distinct
                      efficacy profile: Cobimetinib was efficacious in $50\%$ of
                      the HGG (47d vs 28d in the sensitive subset) and Idanasutlin
                      in $80\%$ of the EP models (79d in the sensitive subset vs
                      52d). The optical imaging signal over time confirmed tumor
                      engraftment at the start of treatment. The most efficacious
                      treatment arms induced growth delay or partial remission.
                      This preclinical validation set gains even more importance
                      using the accompanying molecular profiling data that are
                      available not only for the PDX but also for the donor
                      patient. Together with the breadth and depth of the still
                      growing PDX collection, a unique preclinical platform for
                      the development of drugs as well as companion diagnostics
                      specifically for pediatric brain cancers is now available to
                      the scientific community.},
      ddc          = {610},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)1},
      doi          = {10.1158/1538-7445.AM2023-3524},
      url          = {https://inrepo02.dkfz.de/record/294423},
}