Prostate cancer
Daniel T. Gewirth, PhD

gewirthProstate cancer is the most frequently diagnosed cancer in men. The standard treatment for patients with advanced-stage disease relies on hormone-like drugs that target a single region of the androgen receptor (AR), which is a key protein in the disease. While these therapies often lead to a significant remission, the reprieve is usually only temporary. In most cases the cancer returns because the AR in the tumor has mutated into a hormone-resistant form.

The goal of Dr. Gewirth’s research is to design therapies that circumvent this resistant state. To do this, he plans to develop new types of drugs that target the androgen receptor in a region called the DNA binding domain. Although long considered a difficult therapeutic target, focusing on the DNA binding domain has advantages: it mutates less frequently in prostate cancer and it is crucial for the androgen receptor to function. As a result, drugs that target this region have great potential to continue working even after the cancer has become resistant to conventional drugs. The HWI group is the only one in the world to have determined the X-ray crystal structure of the androgen receptor DNA binding domain and will bring this experience to bear in determining how candidate drugs interact with this domain. 

The outcome of this research has the potential to help all patients who suffer from prostate cancer. It is especially promising for patients whose tumors have become resistant to conventional hormone-mimicking therapies because it may lead to treatments that can be used to prolong their remission. This work would also be a proof of the principle that the androgen receptor could be targeted for therapy in non-conventional ways. It would likely spur other groups to target new regions of this protein, and lead to a broader armamentarium of treatments that might significantly extend the lives of patients suffering from advanced stage prostate cancer.

Dr. Gewirth’s work is supported by a synergy grant, “Development of a new class of drugs to inhibit all forms of androgen receptor in castration resistant prostate cancer,” from the Department of Defense.  His co-investigators are Dr. Paul Rennie from the Vancouver Prostate Centre, and Dr. Scott Dehm from the University of Minnesota.

Crystal structure of the androgen receptor (AR) bound to DNA (PMID 15037741). It is expected that new drugs developed by this project will disrupt protein-DNA binding thereby rendering the AR inactive.
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