IMPaCT Investigator Highlights (Text Version) - Dr. Marianne Sadar
Title: Regression of Castrate-Recurrent Prostate Cancer by Antagonists to the Androgen Receptor N-Terminal Domain
Investigator: Marianne Sadar, PhD
Our grant was to look at small molecules, drugs that were isolated from marine sponges from around the world and look at their effects on the androgen receptor.
The androgen receptor is very important because it mediates the effects of testosterone. Testosterone is the sex hormone that really fuels prostate cancer cells to proliferate and grow.
All current therapies right now in the clinic for advanced prostate cancer target the androgen receptor but they’re targeting it at the wrong end and I actually mean that literally. They’re working at one end and actually they should be working at the other end, because it’s the engine of this protein. We absolutely have to have this region for the androgen receptor to work. So our approach was to develop inhibitors to this region. Our inhibitors directly bind to the N-terminus domain and it causes a change in the shape of this region so that it can't interact with other proteins to be active--to turn on those genes involved in proliferation, to keep the cancer cells alive. So if we can shut this off, the cancer cells will actually die.
So what we did was we started screening these natural compounds libraries, these were marine sponge extracts that have been collected from all around the world. We started screening them for which one is interacting with the N-terminus and which ones seem specific.
And so EPI001 was one of the molecules we pulled out, and one of the tests that we did was we just looked at the activity of this N-terminus domain
When you stimulate prostate cancer cells with forskolin you activate this part of the receptor, the N-terminus. This is shown as this increase in activity here. When you have EPI001 drug you block that activity. So this was a very good assay to show that our molecule really was inhibiting that region.
The anti-androgen bicalutamide that’s used clinically, it had no effect because it works on a ligand-binding domain and this particular assay doesn’t have a ligand-binding domain. So it obviously wouldn’t have any effect.
But the ultimate test is--well does it have any effect on the tumor in animals? So we first tried our drug in mature male mice, so they have testosterone and we put human prostate cancer tumors under their skin and grew these human cancers under their skin, and then we started treating these mice with our drug. So if we look at the volume of the tumor, in our control arm, the tumors still grew very quickly. You have testosterone there that’s really fueling the tumor. And when we added in EPI001 we’re actually holding the tumor in check.
And the tumors actually have a physical appearance that’s very different. They’re not these red--or bloody tumors; they actually turned this whitish color. And so the drug was definitely having an effect on these tumors. But we wanted to test the real situation because in the real situation the patient would be on androgen ablation therapy meaning he would be castrated. And so that was this next set of experiments and so same thing; we had human prostate cancer tumors growing under the skin of mice and we castrated those animals. Seven days later we started injecting animals with our drug. And you can see here that our control arm keeps growing; even though the animals are castrated these tumors are still growing very well. And so we can also see that our drug worked better than castration.
When we treat these animals with our drug, these tumors are actually shrinking and going away. They’re going from 100-percent tumor volume down here to about 35-percent. If we harvested the tumors at these points these are our control tumors and the black bar represents 10 millimeters and this is actually the tumors treated with our drug and they were going away.
I clearly remember the day that my technician brought in the results from the animal studies; my jaw absolutely hit the floor. It was not--not that our compound was just slowing the growth of tumors which is really where the bar is at right now. Most therapies that are being tested in laboratories, they just slow down the growth but the data that my technician showed me was these tumors were going away. They were disappearing. And I still remember that I grabbed the data and flew out of my office [Laughs] and started showing everyone. And it--it just was too good to believe. I never even dared write that in my grant that--that we would find a drug that would actually cause tumors to shrink.
This was the eureka moment when we realized that we may have something that doesn’t just delay the tumors, but we may actually have something that might be curative for these men. Maybe we can make the tumor completely go away.
So we have a drug that we think is worthy of going into the clinic. We have a lot of interest into getting it into the clinic. We’re trying to do the safety and toxicity tests in order to get investigational new drug status--it’s this IND status so we can legally put this drug into patients for clinical trials.