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FDA-approved ferumoxytol displays anti-leukaemia efficacy against cells with low ferroportin levels

Nature Nanotechnology volume 14, pages 616–622 (2019)Cite this article

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Abstract

Acute myeloid leukaemia is a fatal disease for most patients. We have found that ferumoxytol (Feraheme), an FDA-approved iron oxide nanoparticle for iron deficiency treatment, demonstrates an anti-leukaemia effect in vitro and in vivo. Using leukaemia cell lines and primary acute myeloid leukaemia patient samples, we show that low expression of the iron exporter ferroportin results in a susceptibility of these cells via an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron lead to increased oxidative stress and cell death. Ferumoxytol treatment results in a significant reduction of disease burden in a murine leukaemia model and patient-derived xenotransplants bearing leukaemia cells with low ferroportin expression. Our findings show how a clinical nanoparticle previously considered largely biologically inert could be rapidly incorporated into clinical trials for patients with leukaemia with low ferroportin levels.

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Fig. 1: Reduced expression of FPN is a feature of leukaemia cell lines and primary AML samples.
Fig. 2: In vivo treatment of mice having blast crisis CML with ferumoxytol reduces leukaemia burden and improves overall survival.
Fig. 3: Ferumoxytol treatment targets primary AML PDXs with low FPN without harming normal cells.
Fig. 4: Oxidative ferrotherapy through low FPN expression in leukaemia cells.

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The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

References

  1. Almeida, A. M. & Ramos, F. Acute myeloid leukemia in the older adults. Leuk. Res. Rep. 6, 1–7 (2016).

    Google Scholar 

  2. Cancer Facts & Figures 2018 (American Cancer Society, 2018); https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf

  3. Gashaw, I., Ellinghaus, P., Sommer, A. & Asadullah, K. What makes a good drug target? Drug Discov. Today 17, S24–S30 (2012).

    Article  CAS  Google Scholar 

  4. Zong, H. et al. A hyperactive signalosome in acute myeloid leukemia drives addiction to a tumor-specific Hsp90 species. Cell Rep. 13, 2159–2173 (2015).

    Article  CAS  Google Scholar 

  5. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  Google Scholar 

  6. Krug, U., Buchner, T., Berdel, W. E. & Muller-Tidow, C. The treatment of elderly patients with acute myeloid leukemia. Dtsch. Ärztebl. Int. 108, 863–870 (2011).

    Google Scholar 

  7. Guzman, M. L. et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105, 4163–4169 (2005).

    Article  CAS  Google Scholar 

  8. Wen, J., You, K. R., Lee, S. Y., Song, C. H. & Kim, D. G. Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J. Biol. Chem. 277, 38954–38964 (2002).

    Article  CAS  Google Scholar 

  9. Gao, L. et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nat. Nanotechnol. 2, 577–583 (2007).

    Article  CAS  Google Scholar 

  10. Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2, 43ra56 (2010).

    Article  Google Scholar 

  11. Deng, Z., Manz, D. H., Torti, S. & Torti, F. M. Effects of ferroportin-mediated iron depletion in cells representative of different histological subtypes of prostate cancer. Antioxid. Redox Signal 30, https://doi.org/10.1089/ars.2017.7023 (2017).

    Article  CAS  Google Scholar 

  12. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

    Article  CAS  Google Scholar 

  13. Torti, S. V. & Torti, F. M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013).

    Article  CAS  Google Scholar 

  14. Basuli, D. et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36, 4089–4099 (2017).

    Article  CAS  Google Scholar 

  15. Gu, Z. et al. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation. Cancer Res. 75, 2211–2221 (2015).

    Article  CAS  Google Scholar 

  16. Strauss, W. E., Dahl, N. V., Li, Z., Lau, G. & Allen, L. F. Ferumoxytol versus iron sucrose treatment: a post-hoc analysis of randomized controlled trials in patients with varying renal function and iron deficiency anemia. BMC Hematol. 16, 20 (2016).

    Article  Google Scholar 

  17. Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S. & Kalayci, O. Oxidative stress and antioxidant defense. World Allergy Organ. J 5, 9–19 (2012).

    Article  CAS  Google Scholar 

  18. Ashton, J. M. et al. Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells. Cell Stem Cell 11, 359–372 (2012).

    Article  CAS  Google Scholar 

  19. Neering, S. J. et al. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 110, 2578–2585 (2007).

    Article  CAS  Google Scholar 

  20. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  Google Scholar 

  21. Pei, S. et al. Rational design of a parthenolide-based drug regimen that selectively eradicates acute myelogenous leukemia stem cells. J. Biol. Chem. 291, 21984–22000 (2016).

    Article  CAS  Google Scholar 

  22. Tesfay, L. et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 75, 2254–2263 (2015).

    Article  CAS  Google Scholar 

  23. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

    Article  CAS  Google Scholar 

  24. Prousek, J. Fenton chemistry in biology and medicine. Pure Appl. Chem. 79, 2325–2338 (2007).

    Article  CAS  Google Scholar 

  25. Raynal, I. et al. Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10. Invest. Radiol. 39, 56–63 (2004).

    Article  CAS  Google Scholar 

  26. Boros, E., Bowen, A. M., Josephson, L., Vasdev, N. & Holland, J. P. Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles. Chem. Sci. 6, 225–236 (2015).

    Article  CAS  Google Scholar 

  27. Wadhwa, J. et al. Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood 99, 2304–2309 (2002).

    Article  CAS  Google Scholar 

  28. Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotechnol. 11, 986–994 (2016).

    Article  CAS  Google Scholar 

  29. Auerbach, M., Chertow, G. M. & Rosner, M. Ferumoxytol for the treatment of iron deficiency anemia. Exp. Rev. Hematol. 11, 829–834 (2018).

    Article  CAS  Google Scholar 

  30. Yuan, H. et al. Heat-induced radiolabeling and fluorescence labeling of Feraheme nanoparticles for PET/SPECT imaging and flow cytometry. Nat. Protoc. 13, 392–412 (2018).

    Article  CAS  Google Scholar 

  31. Ye, H. et al. Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell 19, 23–37 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the following grants: National Institutes of Health (NIH) R01CA218615 and R01CA215700 (to J.G.), P30 CA08748 (to C. Thompson, MSKCC) and R01CA172546 and R01CA102031 (to M.L.G.), an ALSF for Childhood Cancer Research award (to C.K.), Mr William H. and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center (to J.G. as co-PI). J.G.’s primary affiliation is the Molecular Pharmacology program of Memorial Sloan Kettering Cancer Center with a secondary appointment at its Radiology Department. He also has an appointment at the Pharmacology Program at Weil Cornell Medical College. Affiliations are listed in order of the authors.

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Author notes

  1. These authors contributed equally: Vicenta Trujillo-Alonso, Edwin C. Pratt.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Vicenta Trujillo-Alonso, Hongliang Zong, Andres Lara-Martinez, Mohamed O. Rabie, Gail J. Roboz & Monica L. Guzman

  2. Department of Pharmacology, Weill Cornell Graduate School, New York, NY, USA

    Edwin C. Pratt, Jan Grimm & Monica L. Guzman

  3. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Edwin C. Pratt, Charalambos Kaittanis & Jan Grimm

  4. Small-Animal Imaging Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Valerie Longo

  5. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA

    Michael W. Becker

  6. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jan Grimm

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  1. Vicenta Trujillo-Alonso
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Contributions

V.T.-A., E.C.P., H.Z., C.K., J.G. and M.L.G. devised and conducted experiments and wrote the manuscript. A.L.-M. and M.O.R. performed experiments. M.W.B. and G.J.R. discussed the data and wrote the manuscript. V.L. conducted injections.

Corresponding authors

Correspondence to Jan Grimm or Monica L. Guzman.

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Competing interests

J.G., C.K., H.Z. and M.L.G. have filed pending US patent application 15/759,161 and pending EU application 16,845,094.8 around the therapeutic use of ferumoxytol. C.K. is currently an employee of Alnylam Pharmaceuticals.

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Journal peer review information: Nature Nanotechnology thanks Kamil Kranc and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary Tables 1–4, Supplementary Figures 1–17

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Trujillo-Alonso, V., Pratt, E.C., Zong, H. et al. FDA-approved ferumoxytol displays anti-leukaemia efficacy against cells with low ferroportin levels. Nat. Nanotechnol. 14, 616–622 (2019). https://doi.org/10.1038/s41565-019-0406-1

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