The vast majority of high-risk prostate cancer cases are caused by abnormally high activity of a protein called the androgen receptor. Present in many prostate cells, androgen receptors detect androgen hormones (including testosterone), and in response, turn on or off genes. Genes that are regulated by androgen hormones are critical for the development of the prostate and maintenance of its function. But when the androgen receptor is overly active, which can occur via several different processes in the aging prostate, it can activate genes that can lead to uncontrolled proliferation of prostate cells. This contributes to the development of aggressive prostate cancer.
Inhibiting the androgen receptor to keep it from being overly active has been a mainstay of prostate cancer treatment for many decades. This type of approach is known as androgen deprivation therapy (ADT). Some ADT methods involve drugs that mimic dihydrotestosterone, an androgen hormone that binds to the androgen receptor and makes it active. However, instead of activating the androgen receptor, these hormone-mimicking drugs have an inhibiting effect. Examples of these drugs include an older drug called Casodex, the recently approved Xtandi, and the investigational drug ARN-509. Other ADT drugs in clinical use (such as Proscar or the newer Zytiga) inhibit the activity of enzymes that produce the androgen hormone testosterone in the body. With lower levels of testosterone available to bind to androgen receptors, androgen receptor activity is decreased.
Different forms of radiation therapy are also commonly used to treat prostate cancer. Radiation therapy breaks both DNA strands, a severe type of DNA damage that, if not repaired, can lead to cell death. In patients with high-risk prostate cancer, radiation therapy is often combined with ADT. The benefits of combining ADT and radiation have been demonstrated in multiple large clinical trials, the results of which have made this combination therapy a standard of care. However, until recently, it was not understood why combining two different treatments–one that inhibits androgen receptors and the other that induces DNA damage–produces better results than either treatment alone.
Two groups of researchers, one from the Memorial Sloan-Kettering Cancer Center in New York City and the other from the Kimmel Cancer Center in Philadelphia, solved the mystery of the combination therapy and published their results in the October issue of the journal Cancer Discovery.
Both groups of researchers analyzed the gene activation processes that happen when the androgen receptor binds to dihydrotestosterone. Both groups found that androgen receptors in cells ‘fed’ with dihydrotestosterone activate hundreds of genes, which was already known from previous studies. In fact, the androgen receptor serves as a master regulator of gene expression in prostate cells, both normal and malignant. In these new studies, the scientists discerned a prominent set of genes activated by the androgen receptors that code for proteins heavily involved in the repair of DNA damage. If cells are irradiated (as they are in radiation therapy) and treated with dihydrotestosterone, levels of the DNA repair proteins become very high, and these proteins manage to fix the breaks in DNA induced by irradiation. Moreover, the high levels of some of these proteins actually help the androgen receptor to perform its master regulator function.
However, when prostate cancer cells were subjected to irradiation in the presence of Xtandi or ARN-509, ADT drugs that inhibit the androgen receptor, the repair of DNA damage was inhibited and cells stopped growing or died as a result of accumulated unrepaired damage. This happened because the inhibited androgen receptor failed to boost the cellular production of DNA damage repair proteins in response to irradiation.
These studies, for the first time, show a positive feedback circuit linking androgen hormone action to the DNA damage response and identify a role for the androgen receptor in the repair of DNA damage. The consequences of these new findings are significant, opening up new possibilities for combination treatments of aggressive prostate cancer. New treatments might involve combining ADT with other therapies that induce DNA damage and precision scheduling of ADT treatments and DNA damaging therapies.
Goodwin JF, Schiewer MJ, Dean JL, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. Published online ahead of print October 18, 2013
Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. Published online ahead of print October 22, 2013