Improved 223Ra Therapy with Combination Epithelial Sodium Channel Blockade

Diane S. Abou, Amanda Fears, Lucy Summer, Mark Longtine, Nadia Benabdallah, Ryan C. Riddle, David Ulmert, Jeff Michalski, Richard Wahl, Denise Chesner, Michele Doucet, Nicholas C. Zachos, Brian W. Simons, Daniel L.J. Thorek

Research output: Contribution to journalArticlepeer-review

Abstract

[223Ra]RaCl2 is the first approved a-particle-emitting therapy and is indicated for treatment of bonemetastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here,we investigated the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Using primary human duodenal organoids (enteroids) asin vitromodelsof the functionalgastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ramembranal transport.Radioactivedrugdistributionwas evaluated for lead combinations in vivo and in osteosarcoma and prostate cancermodels.Results:Amiloride shifted 223Ra uptake in vivo fromthe gut and nearly doubled the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent imaging and radiographywas significantly greater than that with single agents alone, and the combination resulted in noweight loss.Conclusion: This combination of approved agentsmay readily be implemented as a clinical approach to improve the outcomes of bonemetastatic cancer patients with the benefit of ameliorated tolerability. COPYRIGHT

Original languageEnglish
Pages (from-to)1751-1758
Number of pages8
JournalJournal of Nuclear Medicine
Volume62
Issue number12
DOIs
StatePublished - Dec 1 2021

Keywords

  • Ra
  • amiloride
  • bone
  • gastrointestinal
  • ion channel

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