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@ARTICLE{Nguyen:301996,
      author       = {N. Nguyen and Y. Min and J. Rivière and M. van der Garde
                      and S. Ghosh and L. M. Bartos and M. Brendel and F.
                      Bassermann$^*$ and A. Azhdarinia and W. A. Weber and K. S.
                      Götze$^*$ and S. Kossatz},
      title        = {{L}imitations of the radiotheranostic concept in
                      neuroendocrine tumors due to lineage-dependent somatostatin
                      receptor expression on hematopoietic stem and progenitor
                      cells},
      journal      = {Theranostics},
      volume       = {15},
      number       = {13},
      issn         = {1838-7640},
      address      = {Wyoming, NSW},
      publisher    = {Ivyspring},
      reportid     = {DKFZ-2025-01195},
      pages        = {6497 - 6515},
      year         = {2025},
      abstract     = {Rationale: Radiopharmaceutical therapy (RPT) has become an
                      effective treatment option for neuroendocrine tumors
                      (NETs)and castration-resistant prostate cancer and is in
                      clinical development for many indications. One of the major
                      advantages oftheranostic RPT is that the distribution of
                      radiopharmaceuticals in the human body can be imaged, and
                      radiation doses to thepatient’s organs can be calculated.
                      However, accurate dosimetry may be fundamentally limited by
                      microscopic heterogeneity ofradiopharmaceutical
                      distribution. Methods: We developed fluorescent analogs of
                      somatostatin-receptor-subtype 2 (SSTR2)targeting
                      Lutetium-177 labeled radiopharmaceuticals that are
                      clinically used in patients with NETs and studied their
                      uptake byhematopoietic stem and progenitor cells (HSPC)
                      using flow cytometry and microscopy. Results: Hematopoietic
                      stem cells (HSCs)and multipotent progenitor cells (MPPs)
                      showed high and specific SSTR2-ligand uptake, which was at
                      similar levels as NET cells.Furthermore, they displayed a
                      several-fold higher uptake of SSTR2-antagonists than of
                      SSTR2-agonists. HSPC treatment with a177Lu-labeled
                      antagonist and agonist showed a stronger reduction of HSC
                      proliferation by the antagonist. Due to the scarcity ofHSCs
                      and MPPs, their contribution to total bone marrow uptake of
                      SSTR2-radiopharmaceuticals is negligible in
                      imaging-baseddosimetry. This likely explains why
                      SSTR2-antagonists caused pancytopenia in clinical trials
                      despite safe dosimetry estimates.Conclusion: Target
                      expression heterogeneity can lead to underestimation of
                      radiopharmaceutical toxicity and should beconsidered when
                      designing clinical trials for new radiopharmaceuticals. The
                      implications of our findings go beyond
                      SSTR2-targetedradiopharmaceuticals and suggest more
                      generally that first-in-human studies should not only be
                      guided by radiation dosimetry butshould also include careful
                      escalation of the administered therapeutic activity. Our
                      multimodal ligand design is modular and canbe applied to
                      other peptide or protein-based radiopharmaceuticals to study
                      cellular distribution and potential bone marrowuptake prior
                      to clinical testing.},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.7150/thno.113354},
      url          = {https://inrepo02.dkfz.de/record/301996},
}