Advertisement

CXCR4-Directed Endoradiotherapy as New Treatment Option in Advanced Multiple Myeloma

  • Constantin Lapa
  • K. Martin Kortüm
  • Ken Herrmann
Chapter

Abstract

Multiple myeloma (MM) accounts for approximately 1% of all cancers and around 10% of hematological malignancies. Although various novel drugs and treatment options including proteasome inhibitors, immunomodulators, antibodies, or the implementation of autologous and allogeneic stem cell transplantation have improved overall survival over the last decades, MM essentially remains an incurable disease. In relapsed/refractory disease, even the most intense treatment regimens frequently fail to efficiently reduce the tumor burden, and patients eventually succumb to their disease.

Given the paramount importance of C-X-C chemokine receptor CXCR4 for both multiple myeloma and bone marrow microenvironment, development of radiolabeled receptor ligands for both CXCR4-directed imaging and therapy has opened new exciting opportunities in the field of radionuclide therapies. Endoradiotherapy can be safely performed as part of the conditioning regimen prior to autologous or allogeneic stem cell transplantation. First experience has hinted at high tumor cell kill in even very advanced MM including extramedullary disease. Further prospective studies to evaluate the efficacy in earlier disease stages are about to be initiated and will also provide further evidence on synergistic multimodality treatment.

Keywords

Multiple myeloma CXCR4 Pentixafor Endoradiotherapy 

References

  1. 1.
    Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–46.CrossRefPubMedGoogle Scholar
  2. 2.
    Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, et al. Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett. 1998;426:271–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, et al. A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur J Cancer. 2013;49:219–30.CrossRefPubMedGoogle Scholar
  5. 5.
    Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Loetscher P, Moser B, Baggiolini M. Chemokines and their receptors in lymphocyte traffic and HIV infection. Adv Immunol. 2000;74:127–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B. CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget. 2015;6:5022–40.PubMedGoogle Scholar
  9. 9.
    Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, Van Camp B, et al. Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival. Haematologica. 2006;91:200–6.PubMedGoogle Scholar
  10. 10.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 2016;35:816–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007;109:2708–17.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 2009;113:4341–51.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hideshima T, Chauhan D, Hayashi T, Podar K, Akiyama M, Gupta D, et al. The biological sequelae of stromal cell-derived factor-1alpha in multiple myeloma. Mol Cancer Ther. 2002;1:539–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Beider K, Bitner H, Leiba M, Gutwein O, Koren-Michowitz M, Ostrovsky O, et al. Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. Oncotarget. 2014;5:11283–96.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Demmer O, Gourni E, Schumacher U, Kessler H, Wester HJ. PET imaging of CXCR4 receptors in cancer by a new optimized ligand. ChemMedChem. 2011;6:1789–91.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gourni E, Demmer O, Schottelius M, D’Alessandria C, Schulz S, Dijkgraaf I, et al. PET of CXCR4 expression by a (68)Ga-labeled highly specific targeted contrast agent. J Nucl Med. 2011;52:1803–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Hartimath SV, Domanska UM, Walenkamp AM, Rudi AJOD, de Vries EF. [(9)(9)mTc]O(2)-AMD3100 as a SPECT tracer for CXCR4 receptor imaging. Nucl Med Biol. 2013;40:507–17.CrossRefPubMedGoogle Scholar
  19. 19.
    Herhaus P, Habringer S, Philipp-Abbrederis K, Vag T, Gerngross C, Schottelius M, et al. Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia. Haematologica. 2016;101:932–40.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vag T, Gerngross C, Herhaus P, Eiber M, Philipp-Abbrederis K, Graner FP, et al. First experience with chemokine receptor CXCR4-targeted PET imaging of patients with solid cancers. J Nucl Med. 2016;57:741–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Bluemel C, Krebs M, Polat B, Linke F, Eiber M, Samnick S, et al. 68Ga-PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-choline-PET/CT. Clin Nucl Med. 2016;41:515.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lapa C, Luckerath K, Rudelius M, Schmid JS, Schoene A, Schirbel A, et al. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer - initial experience. Oncotarget. 2016;7:9288.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Lapa C, Reiter T, Werner RA, Ertl G, Wester HJ, Buck AK, et al. [(68)Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression after myocardial infarction. JACC Cardiovasc Imaging. 2015;8:1466–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Lapa C, Schreder M, Schirbel A, Samnick S, Kortum KM, Herrmann K, et al. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [18F]FDG and laboratory values. Theranostics. 2017;7:205–12.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Philipp-Abbrederis K, Herrmann K, Knop S, Schottelius M, Eiber M, Luckerath K, et al. In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma. EMBO Mol Med. 2015;7:477–87.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lapa C, Schirbel A, Samnick S, Luckerath K, Kortum KM, Knop S, et al. The gross picture: intraindividual tumour heterogeneity in a patient with nonsecretory multiple myeloma. Eur J Nucl Med Mol Imaging. 2017;44:1097–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Herrmann K, Schottelius M, Lapa C, Osl T, Poschenrieder A, Hanscheid H, et al. First-in-human experience of CXCR4-directed endoradiotherapy with 177Lu- and 90Y-labeled pentixather in advanced-stage multiple myeloma with extensive intra- and extramedullary disease. J Nucl Med. 2016;57:248–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O’Dorisio MS, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40:800–16.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lapa C, Herrmann K, Schirbel A, Hänscheid H, Lückerath K, Schottelius M, et al. CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma. Theranostics. 2017;7:1589.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57:1941–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Sathekge M, Knoesen O, Meckel M, Modiselle M, Vorster M, Marx S. 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2017;44:1099–100.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Constantin Lapa
    • 1
  • K. Martin Kortüm
    • 2
  • Ken Herrmann
    • 3
  1. 1.Department of Nuclear MedicineUniversitätsklinikum WürzburgWürzburgGermany
  2. 2.Department of Internal Medicine IIUniversitätsklinikum WürzburgWürzburgGermany
  3. 3.Department of Nuclear MedicineUniversitätsklinikum EssenEssenGermany

Personalised recommendations