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

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

  • Nat Commun. 2023 Nov 25;14(1):7725. doi: 10.1038/s41467-023-43175-5.
Zijian Fang 1 2 3,  Giuditta Corbizi Fattori # 1 2 3,  Thomas McKerrell # 1 3 4,  Rebecca H Boucher 5,  Aimee Jackson 5,  Rachel S Fletcher 5,  Dorian Forte 1 2 3,  Jose-Ezequiel Martin 6,  Sonia Fox 5,  James Roberts 2,  Rachel Glover 2,  Erica Harris 2,  Hannah R Bridges 7,  Luigi Grassi 2,  Alba Rodriguez-Meira 8,  Adam J Mead 8,  Steven Knapper 9,  Joanne Ewing 10,  Nauman M Butt 11,  Manish Jain 12,  Sebastian Francis 13,  Fiona J Clark 10,  Jason Coppell 14,  Mary F McMullin 15,  Frances Wadelin 16,  Srinivasan Narayanan 17,  Dragana Milojkovic 18,  Mark W Drummond 19,  Mallika Sekhar 20,  Hesham ElDaly 4,  Judy Hirst 7,  Maike Paramor 1,  E Joanna Baxter 2,  Anna L Godfrey 4,  Claire N Harrison 21,  Simón Méndez-Ferrer 22 23 24
Affiliations

Affiliations

  • 1 Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • 2 Department of Haematology, University of Cambridge, Cambridge, UK.
  • 3 NHS Blood and Transplant, Cambridge, UK.
  • 4 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 5 Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
  • 6 Cancer Molecular Diagnostic Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK.
  • 7 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • 8 NIHR Biomedical Research Centre and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 9 School of Medicine, Cardiff University, Cardiff, UK.
  • 10 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
  • 11 The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
  • 12 St James University Hospital, Leeds, UK.
  • 13 Sheffield Teaching Hospitals NHS Trust, Sheffield, UK.
  • 14 Royal Devon and Exeter Hospital, Exeter, UK.
  • 15 Queens University, Belfast, UK.
  • 16 Nottingham University Hospital, Nottingham, UK.
  • 17 University Hospital Southampton NHSFT, Southampton, UK.
  • 18 Imperial College Healthcare NHS Trust, London, UK.
  • 19 Beatson West of Scotland Cancer Centre, Glasgow, UK.
  • 20 University College Hospital London, London, UK.
  • 21 Guy's and Saint Thomas' NHS Foundation Trust, London, UK. Claire.Harrison@gstt.nhs.uk.
  • 22 Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK. sm2116@cam.ac.uk.
  • 23 Department of Haematology, University of Cambridge, Cambridge, UK. sm2116@cam.ac.uk.
  • 24 NHS Blood and Transplant, Cambridge, UK. sm2116@cam.ac.uk.
  • # Contributed equally.
PMID: 38001082 DOI: 10.1038/s41467-023-43175-5
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z