Researchers identify lynchpin molecule for prostate cancer metastasis

A single molecule appears to be the central regulator driving metastasis in prostate cancer.
A single molecule appears to be the central regulator driving metastasis in prostate cancer.

Cancer is a disease of cell growth, but most tumors only become lethal once they spread from their first location to sites throughout the body.

For the first time, researchers report that a single molecule appears to be the central regulator driving metastasis in prostate cancer.

The study, published in Cancer Cell (2015; doi:10.1016/j.ccell.2015.06.004), offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well.

“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,” said corresponding author Karen Knudsen, PhD, director of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA, known as mutations, that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to anchor down in a new location, such as the bone, the lungs, the liver, or other organs, where new tumors start to grow.

Although these processes are fairly well characterized, there appeared to be many nonoverlapping pathways that ultimately lead to these traits.

Now, Knudsen and colleagues have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is DNA-PKcs, a DNA repair kinase.

The kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue holding the many broken pieces of DNA together and keeping alive a cell that should normally self-destruct.

The researchers showed that DNA-PKcs appears to act as a master regulator of signaling networks that turn on the entire program of metastatic processes.

Specifically, the DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other gene networks involved in other steps in the metastatic cascade, such as cell migration and invasion.

In addition to experiments in prostate cancer cell lines, Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNA-PKcs production or function.

In mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, the researchers analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels with the patients' medical records.

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They saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

“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,” said Knudsen.

Although not all molecules are easily turned into drugs, at least one pharmaceutical company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase 1 study (NCT01353625).

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