DNA Repair Kinase Identified as Key Driver of Metastasis in Prostate Cancer
Researchers at Thomas Jefferson University reported finding a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published by Goodwin et al 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.
“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 Karen Knudsen, PhD, Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University; the Hilary Koprowski Professor and Chair of Cancer Biology; and Professor of Urology, Radiation Oncology, and Medical Oncology at Jefferson.
'A Master Regulator'
Dr. 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 a DNA repair kinase called DNA-PKcs. The kinase rejoins broken or mutated DNA strands in a cancer cell, 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.
The researchers showed that DNA-PKcs also appears to act as a master regulator of signaling networks that turn on the entire program of metastatic processes. Specifically, 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, Dr. Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, the development of metastases could be blocked 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 patients with prostate cancer for the amount of DNA-PKcs those cells contained and compared those levels with the patients’ medical records. They saw that a spike in the kinase levels was a strong predictor of developing metastases and poorer outcomes in patients with 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 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 Dr. Knudsen.
Inhibitors Under Development
A phase I study studying a drug developed to inhibit DNA-PKcs is underway (NCT01353625). “We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. This new trial will be for patients advancing on standard-of-care therapies and will be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium, of which we are a member,” explained Dr. Knudsen.
“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,” said Dr. Knudsen. “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.”
Dr. Knudsen is the corresponding author of the Cancer Cell article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
