Prostate cancer cells can activate genes associated with bone formation and mimic bone cells’ behavior, allowing them to spread into bones.
Those findings by by Duke University researchers, have revealed that targeting this transformation process may represent an alternative strategy to prevent the progression and metastization of prostate cancer .
The study, “Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer,” was published recently in the journal PLOS ONE.
At advanced stages of prostate cancer, malignant cells spread into other body parts, often the bones. Bone metastases are often associated with a poor prognosis and reduced chances of survival.
Radiotherapy with radium-233 (a radioactive component) selectively targets bone metastases and improves overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC), a difficult-to-treat form of the disease that no longer responds to hormone therapy. Still, the mode of action of radium-233 in the bone remains unknown. Understanding the mechanism behind the benefits obtained with radium-233 would allow researchers to design even more effective therapies to potentially prevent spreading of prostate cancer cells into the bone.
With this in mind, Duke Cancer Institute researchers conducted an early Phase 1 clinical trial (NCT02204943) that enrolled 20 men with symptomatic bone-metastatic prostate cancer who were treated with radium-233.
“Given that most men who die of prostate cancer have bone metastases, this work is critical to helping understand this process,” Andrew Armstrong, MD, the study’s lead author, said in a press release. Armstrong is director of research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. The team analyzed patients’ blood for detection of circulating tumor cells and tissue samples of bone metastasis collected before, and at three and six months, after they underwent radiotherapy with radium-233.
They found that circulating tumor cells were positive for an enzyme called bone alkaline phosphatase, or B-ALP, which is critical for bone formation. Also, a genetic analysis of these circulating tumor cells revealed that they had more copies of seven genes linked with bone formation and of genes known to drive cancer aggressiveness.
To further confirm these findings, the team repeated the analysis but with samples collected from 45 men with mCRPC and bone metastases who took part of the ongoing Prophecy study (NCT02269982). Once again, researchers found increased number of genes involved in bone formation in the collected samples.
Following radiotherapy with radium-233, the radioactive agent was found to be accumulated in bone metastases, suggesting that the therapy was working as expected. Despite this, however, tumor cells were still circulating throughout the body and cancer progressed within six months of therapy.
Interestingly, the team found that these circulating cells were found to have a wide range of genetic alterations that could drive cancer progression and resistance to radium-233 therapy.
Overall, the findings suggest that cancer cells that activate the production of genes involved in bone formation — a process called osteomimicry — allow cells to spread and colonize the bone. But this also may promote the targeting of bone metastases by radium-233.
“Osteomimicry may contribute in part to how prostate cancer spreads to bone, but also to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy,” said Armstrong. However, the action of radium-223 may fall short when targeting circulating tumor cells, which may promote cancer progression over time.
“Our findings support a personalized approach to prevention or targeting of bone metastases in prostate cancer that account for the genetic dysregulation of key plasticity pathways important for bone metastasis and bone targeted therapies,” the researchers stated.
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