Androgen Receptor and Castration-Resistant Prostate Cancer
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.