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Oliver Sartor: Hi, Dr. Oliver Sartor here with Uro Today. Very special guest, Dr. Martin Pomper. I think Dr. Pomper is well known to the field. He's been thinking about the concept of Theranostics for four decades, which is a little bit crazy. He is the chairman of radiology at the University of Texas, Southwestern in Houston, and all-around good guy. So welcome, Martin.

Martin Pomper: Thank you, Oliver. Very kind of you to say.

Oliver Sartor: I'm going to ask you the first question, and for somebody who's been thinking about the theranostic field for four decades, maybe it's a trivial question, but I think our readers want to hear. Why radiopharmaceuticals? What attracts you to this field? What makes it special? Why not CAR-Ts? Why not ADCs? The world is on fire for all these new cancer therapies, and ADCs just sold to Pfizer for $40 billion. Why radiopharmaceuticals?

Martin Pomper: Well, that is the big question of the day. So first, let me start by saying that I have a certain bias toward radiopharmaceuticals because of my background as a chemist. So if I go back to the early '80s when I started out as a graduate student in organic chemistry at the University of Illinois, my thinking was I wanted to apply chemistry to medicine somehow. So in doing that, most of what we worked with were small molecules, and even at that remote time, we were beginning to look at, in the laboratory of John Katzenellenbogen, looking at estrogens and ways of looking at estrogen receptor-positive breast cancer, potentially treating it with an isotope that might be therapeutic. So even literally 40 years ago.

It was appealing to me because it was enabling me to use chemistry toward medicine, and also I like the idea of how easily we can manipulate these small molecules. I like the way that we could bring to bear chemistry to make compounds that have different pharmacokinetic properties, just easier to manipulate than biologicals.

Of course, even back then it was very appealing to think of taking an antibody and attaching an isotope to it, which was done at the same time. Back then, I think that David Goldenberg referred to it as RAID and RAIT, radioimmunodetection and radioimmunotherapy; this is the mid-'80s with Immunomedics. But I always felt that the antibodies were sort of clumsy, and I thought that it was a little bit of a ham-fisted approach because you are sort of at the mercy of what the antibody does once you inject it. It circulates for a long time, potential for getting into the bloodstream for a long time, going into other organs. Whereas with the small molecules, we can actually get in and hit very specific, precise targets like drugs. Maybe turn drugs that have been highly optimized through the tools of medicinal chemistry and change them into molecular radiotherapeutics.

So that's sort of what theranostic is to my mind. Antibody-drug conjugates, I think it's also a great idea. Also, there's that element of specificity. CAR T cells—cells are arguably smarter than drugs, so you're using cells to treat cancer. These are both very powerful techniques. But I think that in theranostics, the way that we think about it, the FDA-approved compounds, these are all small molecules; they really lend themselves nicely to manipulation with respect to pharmacokinetics, the isotope that you use, you can do this in a standard laboratory. These are not biological agents. There's not immunoreactivity.

So I think that the field right now, with the advances that we've had in pharmacogenomics, in animal models of cancer, in isotope production, the remarkable sensitivities that we have of modern imaging technology, molecular imaging technology—all these things have come together now in 2023 such that it's perfect for these molecular radiotherapeutics. And I'm not going to totally discount the larger biologicals, although I am biased toward the smaller biologicals, mainly because of tumor penetration and other things that we could get into if you want.

Oliver Sartor: Thank you very much for that explanation. You have helped to found a company, ZiAlpha, and ZiAlpha has been talking about Astatine-211, an alpha emitter that a lot of people may not be very familiar with. Why Astatine-211? What prompts you to move in that particular isotopic direction?

Martin Pomper: Yeah, great question. I was introduced to Astatine-211 by my longtime collaborator, Michael Zalutsky, when we were on an NIH study section together. I saw a proposal that was using Actinium-225, and I asked him, "What's wrong with Actinium-225?" Seems like a nice, powerful—it's high LET, high linear energy transfer radiation. Back when I was in graduate school, I worked with Auger electron emitters, also high LET. I said, "What's wrong with Actinium?" And then literally he came up to me, and I probably shouldn't say this, but he kicked me in my ankle four times, each time representing another decay of the Actinium-225. He says after that first decay, "You can't control where those other alpha particles are going, and they can be very toxic. You get a recoil effect after that first decay that removes the Actinium from its targeting moiety—the small molecule, the antibody, or whatever—and you lose control, so you're going to have more side effects. Actinium is going to be more toxic."

So that got me thinking about alternatives. Now, the other thing about Astatine, apart from the fact that unlike Actinium, it doesn't have four alpha decays—it really only has one alpha decay—it has a much shorter physical half-life, about seven hours as opposed to 10 days. So there's a better opportunity for lower toxicity. My view of alpha particle emitters is that if you've got an alpha particle emitter, it's going to be great. It's going to work; it's going to be efficacious. You really want to avoid off-target effects, or you want to avoid effects that are going to cause toxicity for the patient. And I think that Astatine, along with Lead-212, these are kind of in that sweet spot where you're not necessarily irradiating for a long time. You don't lose control of downstream alpha particles.

The other thing that I like about Astatine, frankly that hit me before all this other biological stuff, is the fact that it's a halogen and you can incorporate it into small molecules fairly easily without the need for a chelator. And it also doesn't really disrupt the overall chemical structure, and you may still get productive binding to a target for small molecules that you've already optimized using iodine, for example. Now, that's not always 100% the case, and the Astatine-carbon bond is a little weaker than the iodine-carbon bond. But we're always careful to track that and see just how unstable that is.

Astatine is a very interesting element because although it's a halogen, it's got metallic properties too, which could also be leveraged by people that are a lot smarter than I am that can develop new chelators if you had to. So because of its ready ability to be incorporated using fairly well-known chemistry into small molecules, the fact it's got one alpha decay, it's got about a seven-hour physical half-life so you can transport it around like FDG if you want, and it's just something that I think is going to be—there are a number of companies that are currently working to make this more available. You need a high-energy cyclotron to make it, not a standard medical imaging-based cyclotron. So that's a little bit tricky, but Actinium is even harder to get a hold of. I think for Actinium, you've got to worry about quantities of Thorium-229, and I think it takes a while to get the Actinium from that. So I think that even from a supply chain standpoint, Astatine will be good.

Oliver Sartor: Interesting. Very interesting. Now the next question, and I want to very specifically say, I'm not trying to get any proprietary information. Is it possible for you to discuss targets that you might be interested in, or is that considered to be confidential now?

Martin Pomper: Well, I could certainly discuss targets I'm interested in, and I'm not an officer in ZiAlpha, so I could tell you what I think are interesting targets. We're not necessarily pursuing these targets, but I think that a couple that come to mind—the two biggies that are sort of considered pan-cancer in some ways, one of them is semi-pan-cancer—and that's the PSMA and the FAP. So I'll talk briefly about those. Those are obvious targets. Lots of companies working on both these targets.

The PSMA, as you know better than literally anyone, having done the registration trial, the VISION trial, it's effective—sort of room for improvement. The FAP, on the other hand, is something that we don't really have quite as good of a handle on because there, we're not killing the cancer cells directly. You might kill some through crossfire, but it's really the cancer-associated fibroblasts that you're killing.

So you have to have faith in the fact that cancer really needs those fibroblasts to live, and it's a little bit more indirect. We need more work there. Now there are also other targets. Some are obvious like Carbonic Anhydrase IX. So that's something that it's not totally specific to, but it is a good target for clear cell renal cell carcinoma. And we and others have small molecules that will bind to CA IX. Frankly, we've only tested it with imaging in patients so far. We haven't done the therapy yet. We don't even know if our compound is internalized yet, which is sometimes important for therapy. But CA IX is also expressed in other cancers just like PSMA and FAP, not quite as pan-cancer.

Other targets—even the old SSTR2 is another old target that is being repurposed in other cancers, in neuroblastoma or small cell lung cancer. So I think that right now there's a big effort to look at how we can leverage things that have already been in patients.

Other targets—the others would be just strictly conjectural that I would talk. There's one called DLL3 that might be present in neuroendocrine prostate and other cancers like that. CEACAM5 is another target of interest for neuroendocrine prostate cancer, but I mean even FAP is present in neuroendocrine prostate cancer. So what we really need are targets for ovarian, for glioblastoma, for pancreatic cancer, and I'd be a little bit out of my depth to talk about near-term emerging targets in those areas. I haven't studied them carefully, but yeah, I mean another for urothelial cancer, Nectin-4 is one that we've looked at. One of my former post-docs, junior faculty, a guy named Xing Yang who's now in Beijing, he has, I think, the first small molecule Nectin-4 ligand, which has been modestly successful. GPC3 is something for hepatocellular carcinoma, but these are just things that I've read about. These are not things that I have a lot of firsthand experience.

Oliver Sartor: Gosh, Marty, that's really interesting to get your perspective. Let me briefly imagine that you have a crystal ball. I've given you this crystal ball. You can look into it. And over the next five years, what do you see emerging that we don't necessarily have today? In other words, next five years, what are going to be some of the concrete examples of progress that you think we'll be able to report?

Martin Pomper: Sure. So progress. I think if I had a crystal ball, I would look and I would look for targets. The targets are the most important aspect of this whole business. With proteogenomics and high-throughput ways of vetting new targets using organoids or spheroids or whatever the new relevant animal models, single-cell sequencing—we need to find targets that are expressed in sufficient quantities that if we engage those targets, that we will kill the cells that they're expressed from. Of course, they have to be very selective to what we want to hit. It doesn't necessarily have to be cancer. There's other uses for some of these theranostics, like in rheumatologic disorders, but I won't get into that.

I think that we have better ways of synthesizing compounds. I think that we're going to see even easier ways. For example, one of the reasons I became a chemist was to make compounds to treat cancer. Now there's click chemistry, so people that aren't synthetic chemists can make these things. So I think that we're developing new synthetic techniques.

There will be new chelators. I've seen a very creative chelator now that can bind to a large metal as well as a small metal. The large metal might be for therapy; the small metal might be for imaging. I mean, very creative stuff. So chemistry is another area that we're going to work on, and I think having various linkers and various chelators are going to be helpful.

New isotopes are coming out all the time. Scandium is being leveraged to a certain extent. We need to really mine the periodic table very carefully. I think that inorganic chemists are having a heyday right now by doing that. Combinations of therapies—rational combinations—are going to be very important. So combining very rationally what we're doing with molecular radiotherapy with immunotherapy. As you know, Oliver, the Kaplan-Meier curves for the test versus the control arms are very close together, sadly. And I think that we're going to probably need an immune component if we're going to eradicate. I have seen CAR T cells, for example. We made a reporter for a CAR T cell, and we could actually see how the CAR T cells—they hang out at the tumor and how they wipe out that tumor. They don't go anywhere until that tumor is gone. So I've seen the power of the immune system. I think we're going to need to harness that in conjunction with the radiopharmaceutical therapy.

I think that ways of getting the compounds to the tumor—if we want to treat GBM, there are new ways now, very safe ways of disrupting the blood-brain barrier using focused ultrasound and other techniques that may come to the fore. I think that picking the right patients for therapy is going to be important. We can use AI to do that. We can build frailty indices into a patient's medical record, their labs, make sure that they can survive the six courses of therapy. Using AI for picking the right dose for patients, for whether or not dose fractionation is useful. So there's a lot we could do.

Prognosis also is another thing that we're going to start looking at with AI in molecular radiotherapy, adaptive therapies also, and this personalized dosimetry. Then there's radiosensitizers. So there's other things that have been out there that hopefully will be improved upon. So I think that I've just given you a laundry list of about 20 things that—I mean, everybody gets 200 millicuries of Pluvicto. I saw a very interesting slide at a DOE meeting just Friday where it showed Shaquille O'Neal standing next to Simone Biles, and the idea was, "Do we really want to use one size fits all for radiopharmaceutical therapy?" And I think the answer is no. We have to be specific about that.

So many things. The things of interest to me are developing new compounds for new targets, and then there's all the other downstream stuff. There's the chelators, there's dosimetry. There's just so many interesting things. There's so many different people in medicine who can contribute to this field. I'm hoping in the future we'll see the Kaplan-Meier curve in the test group will become horizontal as opposed to dipping down. I predict that that'll happen, but at the very least, people will feel a lot better. At least you and I have seen in our practice how theranostics have really improved people's quality of life, and I just want to see more of that.

Oliver Sartor: Well, Martin, I have just had a brief outline of the next 20 years, and I share with you that optimism, that the horizontal Kaplan-Meier curve will begin to emerge.

Martin Pomper: I hope so.

Oliver Sartor: I simply say thank you so much for being here today. Thank you for sharing your vision, your thoughts. You've been a leader in the field, and I hope the next 40 years are going to be better than the last. So thanks again.

Martin Pomper: I hope so. Thanks a lot, Oliver. It's always a pleasure talking with you. Take care. Thank you.

Oliver Sartor: Bye.