Radium 223-mediated zonal cytotoxicity of prostate cancer in bone

21 January 2019

In preclinical prostate carcinoma in the bone, Rad-223 eradicated effectively micro-tumors but macro-tumors persisted and expanded. The data point to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core.

Peter Friedl, theme Cancer development and immune defense, and colleagues, published these findings in the Journal of the National Cancer Institute (JNCI).

Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Radium-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. In a joint effort between the Radboudumc and the MD Anderson Cancer Center, they show that limited radiation penetrance in situ defines outcome. 
 
They tested the Radium-223 overall response in prostace cancer in mouse bones and applied intravital microscopy and in silico modeling to predict Rad-223 effectiveness in lesions of different sizes. Rad-223 caused profound cancer cell lethality along the bone interface but not the more distant tumor core. In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27,306 cells), further confirmed in vivo tumors in mice. Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. 
 
The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the bone niche together with the tumor core.