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@ARTICLE{Martin:275976,
      author       = {S. Martin and D. Viertl and A. Janz and S. Habringer$^*$
                      and U. Keller$^*$ and M. Schottelius},
      title        = {{I}nfluence of corticosteroid treatment on {CXCR}4
                      expression in {DLBCL}.},
      journal      = {EJNMMI Research},
      volume       = {13},
      number       = {1},
      issn         = {2191-219X},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2023-00956},
      pages        = {40},
      year         = {2023},
      note         = {Short Communication},
      abstract     = {CXCR4-targeted radioligand therapy (RLT) with
                      [177Lu]Lu/[90Y]Y-PentixaTher has recently evolved as a
                      promising therapeutic option for patients with advanced
                      hematological cancers. Given their advanced disease stage,
                      most patients scheduled for PentixaTher RLT require
                      concomitant or bridging chemotherapy to prevent intermittent
                      tumor progression. These (mostly combination) therapies may
                      cause significant downregulation of tumoral CXCR4
                      expression, challenging the applicability of PentixaTher
                      RLT. This study therefore aimed at investigating the
                      influence of corticosteroids, a central component of these
                      chemotherapies, on CXCR4 regulation in diffuse large B cell
                      lymphoma (DLBCL).Different DLBCL cell lines (Daudi, OCI-LY1,
                      SUDHL-4, -5-, -6 and -8) as well as the human T-cell
                      lymphoma cell line Jurkat were incubated with Dexamethasone
                      (Dex; 0.5 and 5 µM, respectively) and Prednisolone (Pred;
                      5 and 50 µM, respectively) for different time points
                      (2 h, 24 h). Treatment-induced modulation of cellular
                      CXCR4 surface expression was assessed via flow cytometry
                      (FC) and compared to untreated cells. A radioligand binding
                      assay with [125I]CPCR4.3 was performed in parallel using the
                      same cells. To quantify potential corticosteroid treatment
                      effects on tumoral CXCR4 expression in vivo, OCI-LY1 bearing
                      NSG mice were injected 50 µg Dex/mouse i.p. (daily for
                      6 days). Then, a biodistribution study (1 h p.i.) using
                      [68Ga]PentixaTher was performed, and tracer biodistribution
                      in treated (n = 5) vs untreated mice (n = 5) was compared.In
                      the in vitro experiments, a strongly cell line-dependent
                      upregulation of CXCR4 was observed for both Dex and Pred
                      treatment, with negligible differences between the high and
                      low dose. While in Jurkat, Daudi and SUDHL-8 cells, CXCR4
                      expression remained unchanged, a 1.5- to 3.5-fold increase
                      in CXCR4 cell surface expression was observed for SUDHL-5 <
                      SUDHL-4 /-6 < OCI-LY1 via FC compared to untreated cells.
                      This increase in CXCR4 expression was also reflected in
                      correspondingly enhanced [125I]CPCR4.3 accumulation in
                      treated cells, with a linear correlation between FC and
                      radioligand binding data. In vivo, Dex treatment led to a
                      general increase of [68Ga]PentixaTher uptake in all organs
                      compared to untreated animals, as a result of a higher
                      tracer concentration in blood. However, we observed an
                      overproportionally enhanced [68Ga]PentixaTher uptake in the
                      OCI-LY1 tumors in treated (21.0 ± $5.5\%iD/g)$ vs untreated
                      (9.2 ± $2.8\%iD/g)$ mice, resulting in higher
                      tumor-to-background ratios in the treatment group.Overall,
                      corticosteroid treatment (Dex/Pred) consistently induced an
                      upregulation of CXCR4 expression DBLCL cells in vitro,
                      albeit in a very cell line-dependent manner. For the cell
                      line with the most pronounced Dex-induced CXCR4
                      upregulation, OCI-LY1, the in vitro findings were
                      corroborated by an in vivo biodistribution study. This
                      confirms that at least the corticosteroid component of
                      stabilizing chemotherapy regimens in DLBCL patients prior to
                      [177Lu]Lu-PentixaTher RLT does not lead to downregulation of
                      the molecular target CXCR4 and may even have a beneficiary
                      effect. However, further studies are needed to investigate
                      if and to what extent the other commonly used
                      chemotherapeutic agents affect CXCR4 expression on DLBCL to
                      ensure the choice of an appropriate treatment regimen prior
                      to [177Lu]Lu/[90Y]Y-PentixaTher RLT.},
      keywords     = {CXCR4 (Other) / Chemokine receptor regulation (Other) /
                      Corticosteroids (Other) / Cortisol (Other) / PentixaTher
                      (Other) / Radioligand therapy (Other)},
      cin          = {BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37162652},
      doi          = {10.1186/s13550-023-00993-4},
      url          = {https://inrepo02.dkfz.de/record/275976},
}