Radium-223 mechanism of action: implications for use in treatment combinations

Michael J. Morris, Eva Corey, Theresa A. Guise, James L. Gulley, William Kevin Kelly, David I. Quinn, Arne Scholz, George Sgouros

Research output: Contribution to journalReview article

Abstract

The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.

Original languageEnglish (US)
Pages (from-to)745-756
Number of pages12
JournalNature Reviews Urology
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Urology

Cite this

Morris, M. J., Corey, E., Guise, T. A., Gulley, J. L., Kevin Kelly, W., Quinn, D. I., Scholz, A., & Sgouros, G. (2019). Radium-223 mechanism of action: implications for use in treatment combinations. Nature Reviews Urology, 16(12), 745-756. https://doi.org/10.1038/s41585-019-0251-x