For advanced prostate cancers, new strategies for therapeutic intervention are urgently needed, and require a better understanding of how tumor cells go from slow growth to aggressive behaviors that threaten patient lives.
A new study, published by Thomas Jefferson University’s Kimmel Cancer Center researchers in the September 11th online edition of the journal Cancer Discovery, showed that hormones promote DNA repair, and that this process is critical for prostate tumor cell survival. The research also revealed a new therapeutic target that has potential for improving management for patients with advanced disease.
“We’ve known for decades that in prostate cancer, disease development and progression are dependent on the action of androgens (testosterone), but the means by which androgens promote these events remain poorly defined,” says lead author Karen Knudsen Ph.D., Professor of Cancer Biology at Thomas Jefferson University and the Deputy Director for Basic Science at Jefferson’s Kimmel Cancer Center. “The concept that androgens assist cancer cells in repairing DNA damage helps to explain how tumors evade therapeutic intervention. The good news is that these discoveries may point toward a new way to treat patients with aggressive disease.”
Inhibiting androgens is the first line of treatment for advanced prostate cancers, but this therapeutic strategy is only transiently effective, generally because tumors develop “rescue” pathways to restore androgen action. To try and understand the implications of this process, and to find means for treating such advanced disease, the researchers identified new molecular pathways involved in relaying messages from the androgen receptor to DNA repair genes. They found that androgens enhanced DNA repair by turning on the gene for a powerful DNA repair enzyme called DNAPK.
When the researchers inhibited DNAPK, they saw a reduction in tumor cell growth, and using disease models, observed that standard therapies were more effective. By acting on a more selective target in the androgen pathway, the researchers hope to improve androgen inhibition strategies and to help patients who no longer respond to androgen-inhibition-based therapies.
“These findings give us new insight into how tumors can evade existing therapies. Most importantly, the fact that prostate cancer cells use androgens and DNAPK to survive therapeutic intervention unveiled an Achilles heel for advanced tumors that we can capitalize on,” said Dr. Knudsen.
The researchers discovered that pharmacologic agents, some of which are already in clinical trials for other malignancies, can be used to suppress DNAPK activity. “The next step for us is to translate these findings into the clinical setting. Luckily, our prostate group is highly collaborative, and we are already in the midst of designing clinical trials to fast-track DNAPK inhibitors into the clinic”, said Dr. Knudsen. “There are always challenges in introducing new therapeutic targets, but if we are correct, there is every reason to believe that DNAPK inhibitors can be used to improve outcomes for patients with advanced disease.”
The study from Dr. Knudsen’s laboratory was a result of an inter-institutional team effort, including contributions of the first author and graduate student Jonathan F. Goodwin, key collaborators from the Thomas Jefferson University Department of Radiation Oncology, Dr. Adam P. Dicker, and Dr. Robert B. Den, and from the University of Michigan, Dr. Felix Y. Feng.
The authors declare that they have no conflicts of interest.
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