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@ARTICLE{Tehranian:169708,
      author       = {C. Tehranian$^*$ and L. Fankhauser$^*$ and P. Harter$^*$
                      and C. D. H. Ratcliffe and P. S. Zeiner and J. M.
                      Messmer$^*$ and D. C. Hoffmann$^*$ and K. Frey$^*$ and D.
                      Westphal and M. W. Ronellenfitsch and E. Sahai and W.
                      Wick$^*$ and M. A. Karreman$^*$ and F. Winkler$^*$},
      title        = {{T}he {PI}3{K}/{A}kt/m{TOR} pathway as a preventive target
                      in melanoma brain metastasis.},
      journal      = {Neuro-Oncology},
      volume       = {24},
      number       = {2},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2021-01515},
      pages        = {213–225},
      year         = {2022},
      note         = {#EA:B320#LA:B329# / Volume 24, Issue 2, February 2022,
                      Pages 213–225},
      abstract     = {Brain metastases (BM) are a frequent complication of
                      malignant melanoma (MM), with limited treatment options and
                      poor survival. Prevention of BM could be more effective and
                      better tolerated than treating established BM in various
                      conditions.To investigate the temporo-spatial dynamics of
                      PI3K/Akt/mTOR (PAM) pathway activation during BM formation
                      and the preventive potential of its inhibition, in vivo
                      molecular imaging with an Akt biosensor was performed, and
                      long-term intravital multiphoton microscopy through a
                      chronic cranial window in mice.In vivo molecular imaging
                      revealed invariable PAM pathway activation during the
                      earliest steps of brain colonization. In order to perform a
                      long-term intravascular arrest and to extravasate,
                      circulating MM cells needed to activate their PAM pathway
                      during this process. However, the PAM pathway was quite
                      heterogeneously activated in established human brain
                      metastases, and its inhibition with the brain-penetrant PAM
                      inhibitor GNE-317 resulted in only modest therapeutic
                      effects in mice. In contrast, giving GNE-317 in preventive
                      schedules that included very low doses effectively reduced
                      growth rate and number of BM in two MM mouse models over
                      time, and led to an overall survival benefit. Longitudinal
                      intravital multiphoton microscopy found that the first,
                      rate-limiting steps of BM formation - permanent
                      intravascular arrest, extravasation, and initial
                      perivascular growth - are most vulnerable to dual PI3K/mTOR
                      inhibition.These findings establish a key role of PAM
                      pathway activation for critical steps of early metastatic
                      brain colonization and reveal its pharmacological inhibition
                      as a potent avenue to prevent the formation of clinically
                      relevant BM.},
      keywords     = {PI3K/Akt/mTOR pathway (Other) / brain metastasis (Other) /
                      dual PI3K/mTOR inhibition (Other) / extravasation (Other) /
                      tertiary prevention (Other)},
      cin          = {B320 / HD01 / FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)FM01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34216217},
      doi          = {10.1093/neuonc/noab159},
      url          = {https://inrepo02.dkfz.de/record/169708},
}