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IMPaCT Investigator Highlights (Text Version) - Dr. Samuel R. Denmeade

Title: Prostate-Specific Membrane Antigen Activated Prodrug and Imaging Agents

Investigator: Samuel R. Denmeade, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

My laboratory focuses on targeted therapies in a way where we’re trying to—to make things inactive until they get into the prostate cancer environment where proteases, which are sort of molecular scissors that can cut proteins into pieces, can activate the—the toxin. And so we’ve looked at drugs that can be activated that way and we’ve looked at proteins.

The original idea of this project was we wanted to find a drug that could kill things without requiring them to grow. Many chemotherapies require cells to be growing. Prostate cancer grows so very slowly we were looking for a drug that didn’t require growth to kill cells. And we found this drug; it’s called Thapsigargin. This is the plant that it comes from; it’s called ThapsiaGarganica. It’s a plant that grows in the Mediterranean as a weed. It’s been known for several thousand years that there was something toxic in this weed, so if sheep or camels or goats ate this weed, they would die.

We were able to harvest the seeds from this plant, extract this compound called Thapsigargin. Thapsigargin kills all cells; it’s not a prostate cancer-specific killer, so the project became how can we take this interesting molecule and make it be a prostate cancer drug? And what—the way we did that was prostate cancer makes discrete proteases. One of them is called prostate-specific membrane antigen and it—it’s a protein that’s on the cell surface. So our idea was we could hook this toxic molecule Thapsigargin to a peptide, a small piece of protein that would be recognized by PSMA on the cell surface. The PMSA would liberate the peptide and the drug. The drug could then go into the cells and kill the cells. Where there wasn’t PMSA the drug would be inactive because the—the peptide tag would still be attached.

The one advantage of this approach is it’s sort of a molecular grenade is what we refer to it as because the cell does not have to make PMSA because this gets activated around the cells—there’s a cell next to it that does not make the target—it would be killed as well. And you know the—the blood vessel supplying the tumor could be killed. There could be a very large bystander effect.

What we had to do to make that happen was to isolate the chemical, modify it chemically, identify specific things that PMSA recognizes, bring that all together, and then do some proof-of-concept studies in animals in the laboratory, et cetera. And we ended up with a molecule that has a peptide piece and a drug piece; the protease can then sequentially remove all of these pieces and liberate the free drug.

And we’ve put this into animals that have human prostate cancers growing in them that make the target. Here we show three different models of human prostate cancer. In each case, we give one dose and you can see that we get this very dramatic effect that lasts for several weeks with just one cycle. Many of the tumors regress and—and a lot of the animals never have the tumor grow back. So we think in some ways we can cure the animals with a single dose.

The drug itself is quite devastating to the tumor. We see large parts of the tumor die off. And then there was an observation that this prostate-specific membrane antigen also may be present in other cancers. And so we’ve looked at a number of cancers and this is work that other people have done as well and we’ve started testing our drug in other cancer types and here we show an example of breast cancer where we get a very profound effect in breast cancer as well based on the fact that this target may be in the cancer.

We learned that when we give the drug that we get very high levels of the drug in the tumor and not very much levels in other tissue. So we did some chemistry to make a labeled drug that we could also image where it went and we have done some imaging in mice to show that we can get some uptake selectively into the tumor that makes the target.

Based on the totality of the work, this technology—platform of an activated drug attracted the interest of a biotechnology company and partnered with them to try to take this into patients to test whether the—all of the stuff with mice is great, but we’re trying to treat men with prostate cancer. And so—after a lot of work on the manufacturing and the scaling up and trying to get lots of seeds into the United States, which was no small task, we started a clinical trial in January of 2010. Currently we’ve treated 15 patients with all types of cancers. Once we learned what the toxic level of the drug is or what the level that we can give to patients, we are then going to do a prostate cancer trial that should be starting later this year where we are just focusing on men with advanced prostate cancer. And so I’m very excited that so far at least the drug has looked like we thought. It hasn’t been toxic to patients. We think we’re getting very close to that level where we’re going to start to see effects on PSA and—and cancer growth, et cetera.

The project was first funded by the Prostate Cancer Foundation and that allowed us to get a little bit of preliminary data to then successfully apply for the—the DoD’s Prostate Cancer Research Program Idea Development Award. That award funded really the critical pieces of this in terms of the research; it’s really been the only grant we’ve had on the project. After we had those critical pieces of data, we were able to get interest from biotechnology to then do the next thing which is take the idea and manufacture the drug and do all the toxicology in animals that the FDA requires to actually get it into people. So the DoD funding was really critical at a critical time, got the critical data out of the grant to be able to transition this to patients.

To get this from an idea in our heads to something that has gone into a patient now. So I think that—I mean that really is the—what the DoD does, this grant process does fantastically well is allow that to happen.