Radium-223, or Xofigo, is an FDA approved bone targeting radiopharmaceutical which improves overall survival in men with bone metastases in castrate resistant prostate cancer. The basis for its clinical benefits has been unknown, how it directly targets the osteoblastic bone microenvironment, for example. We hypothesised that this process of osteomimicry that prostate cancer cells can undergo may explain some of the benefits. Osteomimicry is a form of plasticity in which prostate cancer cells can evolve and acquire a bone forming property. In order to answer this question we studied a group of men treated at our university with radium and we did bone biopsies, circulating tumour cell analyses and cell free DNA analyses and we found evidence in the circulating tumour cells and in the bone of osteomimicry, specifically bone alkaline phosphatase which is an enzyme that is important for bone mineralisation was upregulated in the circulating tumour cells in the majority of men and it persisted, despite the radium, although it declined. Serum bone alkaline phosphatase declines with this therapy and that decline is associated with a better long-term survival. We found that there was genetic evidence of osteomimicry pathways getting amplified in the cell free DNA as well as circulating tumour cells but, interestingly, this was much more easily detected in the CTCs rather than the cell free DNA, possibly because of differences in assay detection but maybe biologic differences in that the circulating tumour cells may have different biologic properties than the shed DNA of dead and dying cells.
Another key finding was that we found that radium uptake and emission, meaning the gamma emission from the bone metastases, was higher in the prostate cancer tumour biopsies themselves rather than in the adjacent normal bone. This supports that radium may be targeting the tumour directly in addition to the bone microenvironment and the osteoblasts. This has implications for the treatment of men with bone metastases: these osteomimicry pathways or plasticity pathways could be co-targeted along with radium or targeted directly in other combinations to prevent or delay bone metastases. Understanding the functional significance of these pathways may help us prevent bone metastases someday and also design better strategies for where radium might be better suited to clinically benefit patients.
This was a 20 patient but very intensive study, so these men underwent up to three biopsies, they had liquid biopsies multiple times during the study. The primary endpoint was actually change in the circulating tumour cell expression of bone alkaline phosphatase, an osteomimicry biomarker, it was not a survival endpoint. It was really a pharmacodynamic study to really intensively look at this biology which did not require a big sample size.
What are the next steps?
What happens next is one of the innovative things out of this project is that we were able to grow some of the circulating tumour cells outside of the bodies of these patients who generously contributed these bone biopsies and circulating tumour cells. We'd like to functionally characterise these osteomimicry pathways to see if we can block them to reduce bone metastases, develop innovative strategies to reduce bone metastases which is the major morbidity of patients who have metastatic prostate cancer.
