Karen Knudsen, PhD
Hilary Koprowski Professor and Chair of Cancer Biology
Professor of Urology, Radiation Oncology, and Medical Oncology
Sidney Kimmel Cancer Center at Thomas Jefferson University
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.
In our research, which was published in Cancer Cell
, we 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.
We demonstrated that that DNA-PKcs has other, far-reaching roles in cancer. DNA-PKcs also 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, we also showed that in mice carrying human models of prostate cancer, we 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, we 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. We 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 DNAPKcs 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.
The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected and the discovery was made possible by key collaborations across academia and industry.
Additional key collaborators on the study included the laboratories of Felix Feng (University of Michigan), Scott Tomlins (University of Michigan), Owen Witte (UCLA), Cory Abate- Shen (Columbia University), Nima Sharifi (Cleveland Clinic) and Jeffrey Karnes (Mayo Clinic), and contributions from GenomeDx. Although not all molecules are easily turned into drugs, at least one pharma company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase I study (NCT01353625).
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. 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.
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 anti-tumor 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.
Goodwin JF, Kothari V, Drake JM et al. DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell. 2015;28(1):97-113.