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<p>The presence of circulating tumor cell (CTC) clusters is associated with disease progression and reduced survival in a variety of cancer types. In breast cancer, preclinical studies showed that inhibitors of the Na<sup>+</sup>/K<sup>+</sup> ATPase suppress CTC clusters and block metastasis. Here we conducted a prospective, open-label, proof-of-concept study in women with metastatic breast cancer, where the primary objective was to determine whether treatment with the Na<sup>+</sup>/K<sup>+</sup> ATPase inhibitor digoxin could reduce mean CTC cluster size. An analysis of nine patients treated daily with a maintenance digoxin dose (0.7–1.4 ng ml<sup>−1</sup> serum level) revealed a mean cluster size reduction of −2.2 cells per cluster upon treatment (<i>P</i> = 0.003), meeting the primary endpoint of the study. Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell–cell adhesion and cell-cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity. No treatment-related adverse events occurred. Thus, our data provide a first-in-human proof of principle that digoxin treatment leads to a partial CTC cluster dissolution, encouraging larger follow-up studies with refined Na<sup>+</sup>/K<sup>+</sup> ATPase inhibitors and that include clinical outcome endpoints. ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/ct2/show/NCT03928210">NCT03928210</a>.</p>

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Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月24日

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  • Christian Kurzeder,
  • Bich Doan Nguyen-Sträuli,
  • Ilona Krol,
  • Alexander Ring,
  • Francesc Castro-Giner,
  • Manuel Nüesch,
  • Simran Asawa,
  • Yu Wei Zhang,
  • Selina Budinjas,
  • Ana Gvozdenovic,
  • Maren Vogel,
  • Angela Kohler,
  • Cvetka Grašič Kuhar,
  • Fabienne D. Schwab,
  • Viola Heinzelmann-Schwarz,
  • Walter Paul Weber,
  • Christoph Rochlitz,
  • Denise Vorburger,
  • Heike Frauchiger-Heuer,
  • Isabell Witzel,
  • Andreas Wicki,
  • Gabriela M. Kuster,
  • Marcus Vetter,
  • Nicola Aceto

摘要

The presence of circulating tumor cell (CTC) clusters is associated with disease progression and reduced survival in a variety of cancer types. In breast cancer, preclinical studies showed that inhibitors of the Na+/K+ ATPase suppress CTC clusters and block metastasis. Here we conducted a prospective, open-label, proof-of-concept study in women with metastatic breast cancer, where the primary objective was to determine whether treatment with the Na+/K+ ATPase inhibitor digoxin could reduce mean CTC cluster size. An analysis of nine patients treated daily with a maintenance digoxin dose (0.7–1.4 ng ml−1 serum level) revealed a mean cluster size reduction of −2.2 cells per cluster upon treatment (P = 0.003), meeting the primary endpoint of the study. Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell–cell adhesion and cell-cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity. No treatment-related adverse events occurred. Thus, our data provide a first-in-human proof of principle that digoxin treatment leads to a partial CTC cluster dissolution, encouraging larger follow-up studies with refined Na+/K+ ATPase inhibitors and that include clinical outcome endpoints. ClinicalTrials.gov identifier: NCT03928210.