Fang, Zijian, Corbizi Fattori, Giuditta, McKerrell, Thomas, Boucher, Rebecca H., Jackson, Aimee, Fletcher, Rachel S., Forte, Dorian, Martin, Jose-Ezequiel, Fox, Sonia, Roberts, James, Glover, Rachel, Harris, Erica, Bridges, Hannah R., Grassi, Luigi, Rodriguez-Meira, Alba, Mead, Adam J., Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441, Ewing, Joanne, Butt, Nauman M., Jain, Manish, Francis, Sebastian, Clark, Fiona J., Coppell, Jason, McMullin, Mary F., Wadelin, Frances, Narayanan, Srinivasan, Milojkovic, Dragana, Drummond, Mark W., Sekhar, Mallika, ElDaly, Hesham, Hirst, Judy, Paramor, Maike, Baxter, E. Joanna, Godfrey, Anna L., Harrison, Claire N. and Méndez-Ferrer, Simón 2023. Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis. Nature Communications 14 , 7725. 10.1038/s41467-023-43175-5 |
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Abstract
Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Medicine |
Additional Information: | License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access |
Publisher: | Nature Research |
ISSN: | 2041-1723 |
Date of First Compliant Deposit: | 27 November 2023 |
Date of Acceptance: | 2 November 2023 |
Last Modified: | 27 Nov 2023 14:45 |
URI: | https://orca.cardiff.ac.uk/id/eprint/164404 |
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