Monday, August 31, 2015

High Levels of DNA-PKcs Can Lead to Metastasis of Prostate Cancer

Medical News Today:
For the first time, a single molecule has been identified that could be central to the mechanism of spread by prostate cancer.

The study is published in the journal Cancer Cell and was completed by researchers from the Thomas Jefferson University in Philadelphia, PA. The results offer a target for the development of a drug that could prevent metastasis in prostate cancer - and possibly other cancers, too.

Karen Knudsen, PhD, director of the Sidney Kimmel Cancer Center at Thomas Jefferson University, says that "finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins."

Dr. Knudsen adds:
"These results strongly suggest that DNA-PKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumors may go on to metastasize."

A tumor undergoes a number of DNA mutations that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to stay at a new location and form a new lump.

Dr. Knudsen and team have shown that DNA-PKcs molecule appears to be central to many of the processes required for a cancer to spread. The DNA repair kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct.

Previous studies have demonstrated a role of DNA-PKcs in resistance to prostate cancer treatment but it may have other, far-reaching roles in cancer.

Specifically, the researchers found that DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other steps.


Mouse studies

As well as investigating prostate cancer cell lines, the team also did work in mice as models of human prostate cancer. Using agents that suppress DNA-PKcs production or function, the researchers could block the development of metastases. In mice with aggressive human tumors, an inhibitor of DNA-PKcs also reduced the overall tumor burden in distant sites of cancer spread.

Dr. Knudsen and team then analyzed DNA-PKcs in human disease through 232 samples taken from prostate cancer patients. They analyzed the amount of DNA-PKcs in cells and made a comparison with medical records. A spike in the kinase levels was a strong predictor of cancer spread and poorer prostate cancer prognosis.

DNA-PKcs was also found to be much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

Pharmaceutical development under way

A drug has already been developed that inhibits DNA-PKcs - it is being tested in early clinical trials.

Dr. Knudsen explains: "We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as antitumor agents.

In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier. Given the role of DNA-PKcs in DNA repair as well as control of tumor metastasis, there will be challenges in clinical implementation, but this discovery unveils new opportunities for preventing or treating advanced disease."

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