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Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Published version
Peer-reviewed

Repository DOI


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Authors

Fang, Zijian 
Corbizi Fattori, Giuditta 
Boucher, Rebecca H 
Jackson, Aimee 

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.

Description

Acknowledgements: We thank the patients and their families for making this study possible; the support by Blood Cancer UK under the Trials Acceleration Programme (TAP) and the Trial Steering Committee members T. Sommervaille, S. Ali and J. Lambert for study design, data collection, and analysis; C. Fielding, H. Matsubara, C. Bernardo-Castiñeira, A. Sommerschield and members of the S.M.-F. group for help and discussions; J. Carroll, B. Huntly, J. Li, and A.R. Green for critical advice and support; Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; D. Bexheti and R. Houghton (Cancer Research UK) for LC-MS/MS. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust - MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. Z.F. was supported by CSC-Cambridge Trust Scholarship. T.M. was supported by NIHR Starter Grant for Clinical Lecturers (SGL018/1032). D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Società Italiana di Ematologia (SIE) and Associazione “Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS” and AIL Bologna ODV. H.R.B. and J.H. were supported by the Medical Research Council (MC_UU_00015/2). S.M.-F was supported by the National Health Service Blood and Transplant (United Kingdom). S.M.-F was supported by European Union’s Horizon 2020 research (ERC-2014-CoG-648765). S.M.-F was supported by MRC-AMED grant MR/V005421/1. S.M.-F was supported by a Programme Foundation Award (C61367/A26670) from Cancer Research UK. This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Keywords

Humans, Myeloproliferative Disorders, Janus Kinase 2, Hematopoietic Stem Cells, Signal Transduction, Neoplasms, Tamoxifen, Mutation, Calreticulin

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
Italian Association for Cancer Research (AIRC) (Fellowship Rif. 20930)
MRC (MR/V005421/1)
Cancer Research UK (A27831)
Cancer Research UK (C61367/A26670)
NHS Blood and Transplant (NHSBT)
European Research Council (648765)
Wellcome Trust (203151/Z/16/Z)
MRC (MC_UU_00015/2)
Medical Research Council (MC_PC_17230)
Medical Research Council (MC_UU_00015/7)
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