Internal medicine

Tumor microenvironment

Mechanism of action

Prostate cancer

Radium-223

Bioinformatics

Biology

Cancer

Oncology

Cytotoxic T cell

In vitro

Immunology

Combination therapy

Bone metastasis

Cancer research

Biochemistry

Medicine

Immune system

Nature Reviews Urology

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. In this Review, Morris et al. summarize the mechanisms through which 223Ra exerts its biological effects in metastatic castration-resistant prostate cancer, discuss potential 223Ra combination therapies and provide future perspectives for targeted alpha-particle therapy.

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