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IMPaCT Investigator Highlights (Text Version) - Dr. Scott Dehm

Title: Androgen Receptor and Castration-Resistant Prostate Cancer

Investigator: Scott Dehm, PhD; Masonic Cancer Center of the University of Minnesota

The focus of my lab’s research is the role of the androgen receptor in prostate cancer progression. Taking away androgens or inhibiting the activity of the androgen receptor with anti-androgens is the standard therapy for metastatic or locally advanced disease. Initially this therapy is quite effective but with time, the disease will eventually recur and start growing again in this castration-resistant phenotype and it’s this stage of the disease that’s the lethal form of prostate cancer.

One of the things that we’ve been interested in identifying is how the androgen receptor is active at this stage of the disease. It’s counterintuitive but the androgen receptor is actually active even though these men are being treated actively with therapies designed to inhibit this particular protein. And so there are changes occurring in this target for therapy that are allowing it to evade therapeutic intervention. We’re pursuing the concept that there are forms of the androgen receptor that can be made that are completely resistant to traditional therapies targeted to the androgen receptor.

Therapies that we have for prostate cancer are targeted to a specific region of the androgen receptor protein to one end of the protein. And what’s very interesting is that it appears as though a subset of castration-resistant prostate tumors have evolved and found a way to eliminate this part of the protein and so you can think of it as all the selective pressure for these tumors is being placed on one particular part of a protein, and the tumor has found a way to eliminate this part in order to continue growing and surviving. And so we’re trying to understand how widespread this phenomenon is and in what subset or percentage of human tumors does this particular phenomenon occur; we’re also interested in trying to understand how this happens and so that we might be able to develop new markers for prostate cancer progression and perhaps be able to identify ahead of time whether a particular man will be able to show a favorable response to a traditional prostate cancer therapy or some of the emerging prostate cancer therapies that are being developed and being discussed at this meeting.

The discovery of androgen receptor alternative splicing leading to the synthesis of these new forms of the androgen receptor that are missing the part of the protein the drug binds to was a very surprising and serendipitous discovery. We were certainly not expecting to see this when we were in the lab performing these experiments. But the experiments that we did perform were sufficiently well-designed and well-controlled that as soon as we were able to identify this as a possible mechanism we were able to chase that idea fairly rapidly and come to some pretty significant conclusions.

Since that initial serendipitous discovery, several other groups have come up with similar stories which validates this work and that’s always very rewarding because any time your own work can get validated by other people it makes you more confident that what you’re seeing could really be an important phenomenon.

So this new finding really does suggest that all the therapies that we have for prostate cancer that are targeted to this particular part of the androgen receptor protein might as a group be less than ideal, and we need to maybe refocus our efforts on hitting another part of the androgen receptor protein as a therapy for prostate cancer. So we know that even though these prostate tumors evade androgen depletion therapy the androgen receptor is still a critical molecule and an important target that we need to think about inhibiting in prostate cancer. And if we can do this more effectively, I think we’ll be able to come up with a more durable and long-lasting treatments for men with advanced prostate cancer.

And so we’re—we’re focusing our energies on trying to identify other regions of the androgen receptor that are important for its function. What are the regions of this protein that make it tick? And the idea is if we can learn enough about the function of these other regions of the androgen receptor we might be able to come up with ways to inhibit this protein which would represent a novel departure from what’s conventionally done in men with castration-resistant disease.

I think it’s critical in this day and age to be a collaborative scientist. We collaborate to obtain tissues that represent the stage of the disease that we’re interested in studying. We collaborate to bring novel methodologies to play and to bear on our lab’s work. We collaborate so that we can test our ideas in new model systems, particularly in xenograft-based models. So for my Department of Defense New Investigator Award, Dr. Bob Vessella at University of Washington serves as my official collaborator and he’s developed many xenograft-based models of prostate cancer progression. Specifically, he has matched pairs of androgen-dependent, treatable prostate tumors, as well as tumors derived from those that have progressed to this lethal castration-resistant stage. These tumors are continually propagated in mice and serve as an important resource for the prostate cancer research community and we are actively pursuing our ideas in those model systems and we’re starting to make important discoveries there as well.