GU Cancers 2018 | Understanding bone metastases formation in patients with prostate cancer

The vast majority of men with metastatic prostate cancer have bone metastases, and most men who pass away from prostate cancer do so because of those bone metastases. So it’s a very pressing problem leading cause of the morbidity of this disease. Osteomimicry is an idea that prostate cancer cells become like bone forming cells and that may explain their particular tendency to spread to the bone. It’s been validated in preclinical models of prostate cancer where prostate cancer tumor cells can actually become like bone forming cells but has not been validated clinically.
We sought to validate that in a small study of patients undergoing radium-223 therapy, where we would do bone biopsies as well as circulating tumor cell biopsies from these men and follow them over time, and what we observed was clear evidence of osteomimicry in the circulating tumor cells, and that was accompanied by a really interesting finding, was enhanced radium uptake in the areas of the tumor cells directly in the bone. We suggest that this osteomimicry may in part, explain how radium works in the bone to improve survival.
Osteomimicry right now is an observation, we don’t yet understand its underlying molecular mechanisms, one of the things that we sought to identify was how does this osteomimicry occur. First we found evidence of alkaline phosphatase, a bone marker expression in the tumor, but we also found genetic evidence of extra copies of genes that regulate the factors of osteomimicry itself in the tumor, so there were several genes that are classically osteoblastic genes there were apparently expressed in the tumor cells themselves and so that suggests some novel pathways that may be targetable for therapies to delay or prevent bone metastasis, so if you can develop drugs that block osteomimicry pathways, this form of plasticity, the cellular plasticity is really important in promoting metastasis itself, so if the goal is to prevent metastasis and that’s the fatal outcome.
This suggests a way forward, it’s certainly a challenge to treat men with metastatases, bone metastases are an intrinsically resistant area where it’s been very difficult to eradicate the tumor from the bone many patients have responses to androgen receptor inhibitor therapy like apalutamide or enzalutamide, abiraterone, and chemotherapy, but bone metastases are particularly refractory, so understanding the biology of bone metastases may allow us to develop strategies that can prevent that in the first place.
We had several findings that support osteomimicry. One is that bone alkaline phosphatase is expressed in the tumor cells directly and we found heterogeneous evidence of this in patients and that these circulating tumor cells bearing this hallmark of osteo mimicry persisted despite the radium 223 so even though patients had a decline in their serum bone markers and had a response to the therapy and a palliative benefit most patients did progress and this osteo mimicry persisted despite a bone targeting therapy we also found genetic evidence so the circulating tumor cells we isolated we were able to extract the DNA and find that compared with the germline there were extra copies of key osteomimetic pathways, so these are pathways such as RANK ligand or osteopontin that regulate osteomimicry itself.