Cancer is a disease of cell growth, but most tumors only become lethal once they metastasize or spread from their first location to sites throughout the body. For the first time, researchers report a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published in Cancer Cell, offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well.
Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA - 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 non-overlapping pathways that ultimately lead to these traits.
Now, researchers have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is a DNA repair kinase called DNA-PKcs. The 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. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments. Importantly, the researchers showed that DNA-PKcs has other, far-reaching roles in cancer.
The researchers showed that DNA-PKcs also appears 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, the researchers 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. And 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 to the patients' medical records. 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.
A DNA-PKcs inhibitor is currently tested in a phase 1 study. This new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumor agents. Using the kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, and treating them with more aggressive therapy earlier.
Based on material originally posted by Thomas Jefferson University.