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Progress Report: Scott Dehm, Ph.D

Investigator: Scott Dehm, PhD – Assistant Professor, University of Minnesota

Mechanisms of Androgen Receptor (AR) Activation in Prostate Cancer

The standard first line treatment strategy for metastatic prostate cancer is androgen (male hormones) deprivation therapy, such as Lupron, which reduces the level of circulating testosterone (type of androgen), or such as Casodex, which directly blocks the activity of the androgen receptor (AR). This therapy is initially effective in the majority of prostate cancer patients because prostate cancer cell growth and survival is largely dependent upon the activity of androgens and AR. However, with time patients inevitably become resistant to these therapies and enter a lethal, castration resistant prostate cancer stage.

AR physically binds to androgen inside of prostate cancer cells, which induces AR to migrate to DNA (genetic code) and activate many genes involved in the disease progression process. Dr. Dehm’s research focuses on understanding how AR present in patients who no longer respond to medications such as Lupron and Casodex remains active.

Dr. Dehm and colleagues have discovered AR variants (modified AR proteins) that lack the surface area which normally interacts with androgen. Since these variants are identical to “normal” AR but no longer bind androgen they are able to cause cancer progression in the absence of androgen and continue to drive the progression of the disease. In his second year as a PCF Young Investigator he has further characterized these AR variants in human prostate cancer specimens. The analysis of 58 specimens of metastatic prostate cancer from 14 patients revealed that in many metastatic lesions, but not all, there were different types of AR variants that are likely responsible for maintaining cancer cell growth. Dr. Dehm is currently developing methodology to measure the different types of AR variants and the quantity of AR variants in patient tumors. The purpose is to determine whether certain types of AR variants confer a worse prognosis. The ultimate goal is to identify new targeted therapies that inhibit AR variants for patients that cease to respond to current androgen deprivation medications.