Putting Quality Over Quantity with Radioligand Therapy

Chuck: This is the Good News About Cancer. I'm Dr. Chuck Ryan.

Alicia: And I’m Dr. Alicia Morgans. 

Chuck: We're oncologists, and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than ever, and we're here to share that with you.

Alicia: In each episode of this show, we talk with one of our colleagues about a promising development in oncology. We'll break down what's new, why it matters, and how it points the way forward.

Michael: I think that we are in a special period right now for radiopharmaceuticals, that if you took flight as an analogy, we're in that period between the Wright brothers and space travel.

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Chuck:  Well today, Alicia, I'm pretty excited about our episode because number one, we're interviewing a longtime colleague and friend. Number two, we're talking about the disease that we treat, prostate cancer. And number three, we're talking about a real advance that has the potential to affect a lot of people with a lot of different cancers in the future. And it's really exciting.

Alicia: It is really exciting and I think particularly for us, with all of the shows that we've done, we have not focused on prostate cancer. So it's a wonderful opportunity to not only talk to somebody that we work with on a regular basis, but also to talk about a disease that we ourselves treat. And in this case, we're talking about radioligand therapies.

Chuck: So what that is, is the ability to deliver a small, almost an atom – like one isotope – one atom of radioactivity to a cancer cell by docking it on a molecule that serves as a vehicle essentially, to deliver radiation right to the cancer cell. And so that involves complicated chemistry. It involves identification of radiation isotopes. It's a whole new way to treat cancer – or is it?

Alicia: Well, actually, this kind of therapy has been around for over a hundred years.

Chuck: The technology now is that we can hand deliver the radioisotope directly to the surface of the cancer. And that's the big innovation.

Alicia: Agreed. And it's not just prostate cancer, some neuroendocrine cancers and others are things that we can target today with more on the way, I think. 

So let's talk to Dr. Michael Morris. He's a medical oncologist at Memorial Sloan Kettering Cancer Center, a colleague of yours and a good friend and colleague and collaborator of mine as well.

He has been working on treating prostate cancer by delivering these radioactive molecules, these radioligand therapies, directly to prostate cancer cells. Let's hear our conversation.

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Chuck: Michael Morris, it’s great to have you on the podcast. 

Michael: Chuck and Alicia, thanks so much for having me.

Alicia: Well, thank you Michael. 

I wonder if you could share with the audience a little bit of background on what these radioligand therapies are – what are these radioisotopes that make them function, and how have they sort of developed generally in cancer care and in nuclear medicine over the last few decades?

Michael: Sure. Let's go back even further than that. Over a century ago, we learned that cancer is susceptible to radiation in a really unique way that distinguishes itself from the normal cells of the body. 

Cancer cells tend to die much more easily when exposed to radiation than normal cells in the body, and so you can use radiation to selectively kill cancer while not killing normal tissue.

And if you trace the history of how radiation has been applied, it is a history of increasing precision. To deliver more and more radiation in an increasingly specific, targeted way so that only the cancer cells – in as much as is possible – receive the radiation to reduce the amount of damage that the normal tissues sustain. 

And in today's day and age, that precision is at the level of the individual cell. Which is a remarkable increase when you think about how radiation used to be delivered in the 1940s and fifties, to ever more precise sources of external beam radiation therapy in the eighties and the nineties, and the use of radioactive seeds to place them in tumor beds to even get more precise.

But now what we can do is we can deliver, by vein, sources of radiation that specifically travel to the cancer cells and then irradiate those cells that they're attached to. Because each molecule of the drug contains a tiny molecule of radioactive substance that only delivers radiation a few cell lengths long. 

And so you're able to deliver the radiation now not just by very precise beam outside the body, or the delivery of radioactive pellets to inside the body, but now deliver on a molecular level to individual cancer cells, a molecule of radiation to destroy that cell and some of the neighboring cells around it. 

Alicia: And there are multiple cancers that right now can receive radioligand therapies – like prostate cancer and some neuroendocrine cancers – and there are probably more that will come in the relatively near future. 

But let’s back it up – Michael, how did we figure out how to deliver this treatment in the first place? How exactly does it work? 

Michael: Let's talk about the first radioligand therapy that there was, because it was a brilliant idea and it still strikes me how clever it is. So that was for metastatic thyroid cancer. You know, although you could try to develop different chemotherapeutics to treat thyroid cancer, you have to figure out how to kill a thyroid cell, basically.

But the whole work of a thyroid cell is to make a hormone that is at its core iodine. And the folks who developed this in the 1950s thought, ‘Well, why don't we just give them radioactive iodine? And iodine collects in the thyroid, relatively uniquely, and we will use the business of the thyroid to treat the cancer by incorporating radioactive iodine and essentially irradiating itself.’

And no matter where the thyroid cancer is – it may be in a portion of the lung because it has metastasized – it's still behaving like a thyroid cell and trying to collect iodine. And so it too, regardless of location, would die because it's incorporating that radioactive material into itself.

In prostate cancer, we used a similar type of thing by using the cancer's biology – of itself – in targeting bone. This was a while ago, about 10 years ago in fact.  And what we did was, develop a radioactive molecule that's taken up by bone metastases in the process of building out dense bone, which is what a prostate cancer cell does when it goes to bone. And most prostate cancers go there.

So basically, we gave patients by vein something that substitutes for calcium, called Radium 223. So come to the future now where we are leveraging the prostate cancer cell itself, you know, as its own biology to deliver radiation. That's been done in other diseases too, such as a neuroendocrine disease at the GI tract.

So, you know, over the course of the decades, building on the shoulders of those who have preceded us, we've gotten ever more sophisticated in getting to the cancer cell itself. And then killing that cancer cell and the ones around it.

Chuck: So even though it's been around for a hundred years, as you kind of point out, we are still sort of at the beginning of this targeting of radiation.

Michael: We are.

Chuck: So, you know, we can say both it is old and new at the same time. 

Michael: That's true of so many things, isn't it?

Chuck: Right, right. Well it's new technology applying an old observation.

And, you know, I remember when Radium was first approved, that Oliver Sartor, who was presenting it, I remember him, he was giving a talk and he put up a paper from the journal Science in 1905, a paper by Marie Curie that basically said radium could one day be used to treat cancer. And I think this was in 2010. And I was like, okay, well you know, we talk about how things take a while to get done in clinical research in cancer. And that was 105 years. So hopefully not so slow in the future.

But you know, it is worth reiterating that it is, I think to many out there listening, quite wild to think about the fact that we can take something like radioactive material, which, you know, we see in the movies and all this other stuff and, and we can just plop it in somebody's vein and it can treat their cancer – quite safely, I might add. 

Michael: Yeah, I think that we are in a special period right now for radiopharmaceuticals. That if you took flight as an analogy, we're in that period between the Wright brothers and space travel, right?

Where you see this, let's say Da Vinci in 1600, you know, sketched out his helicopter, and it took another several centuries to get to the point where the Wright brothers could have a few seconds of flight. But then several decades later, we were on the surface of the moon.

So we now have the technology to understand the properties of the different targeting molecules, the linkers that attach them to the payloads – these radioactive molecules – the nature of those payloads. And we understand now, ‘Oh wow, there are limitless possibilities here.’

That now the chemistry is in place, the physics are in place, we have the patient understanding and the biology of the diseases to be in place. So there's a huge amount of innovation and invention now, that was only a matter of speculation and fantasy then. 

Like when Madame Curie would say, you know, ‘I think there's something that we could do about cancer.’ Right? That's the Da Vinci moment.

You know? And, and, and now we have the full manifestation of the tools needed to create all of these new drugs really quite quickly and cheaply.

And there's a true explosion of both academic interest and commercial interest. I, I, I never would've imagined that we would be in a day like this, but it's really quite incredible the intellectual explosion that we're seeing in terms of how to treat cancer this way.

Chuck: So I think many patients may be taken aback and even concerned about this idea of having radiation injected into their veins. And you just made a nice description of why that might be different. But what does the patient actually go through when they get the treatment?

Michael: Sure. So the first thing that probably happens well before treatment is they get a scan that is called a PET scan, that allows us to see whether their cancer is amenable to this type of therapy. And what that PET scan basically is doing is illuminating the biology of their cancer. 

So we want to make sure that that target is actually in place for that given patient. That way, we're not giving this therapy to people who wouldn't benefit from it. And we can also predict how well the treatment is going to work by virtue of how much of that target is in the cell on the PET scan.

Think about how different that is from most of our other treatments. Generally, what we'll say to a patient getting any kind of treatment for any cancer, we'll say ‘You have a certain percent likelihood of responding to it, and we're just going to try it because based on an educated guess – or educated data set – people like you tend to have this type of disease. So we'll give you this drug and we'll see whether it works or not.’ 

Here, what we are first of all saying is, ‘If you don't have these features on your PET scan, we're not going to give you this treatment at all. You're going to move on to something that's more likely to work. Because we can tell right up from the get go that you are not going to benefit from this drug. You don't have the target that we're aiming for. We won't be delivering any radiation.’

So that's a huge benefit to spare someone, especially if they have advanced disease, a waste of time receiving a treatment that isn't going to benefit them.

In terms of the actual mechanics of treatment, it's really very straightforward. Treatment just involves walking into a special kind of facility, which has protection against radiation. And you get an IV placed, you get some medicine to prevent GI upset, and some hydration. And then you get treated, and then you go home. And that really is about it. 

There are some precautions that we ask patients to take for a couple of days in terms of managing urine and stool, but it really is very straightforward treatment in the sense that the drug is doing the work, right. The drug is circulating around the body, it's finding the cancer cells. It then gets excreted out, usually in the urine, and then that's it.

Chuck: And the precautions are because you presumably have a little bit of radiation in your urine for a couple days while it's clearing out of the body.

Michael: That's right. Exactly. 

Alicia: So one of the other pieces of good news that I think comes along with this type of therapy is that it allows us to incorporate those experts in imaging into our care team. And I think patients have been really happy in cancer care to know that they can have a surgeon perhaps, or a radiation doctor, and a medical oncologist all working together. And they understand that a pathologist who's looking at their cancer under the microscope and a radiologist who is looking at the images in general can be helpful. 

But this brings in another person, this group of people in nuclear medicine who are specialists in reading the scans that are the weather map that help us know where the cancer is. And helping to better support people across the many needs that they might have.

Michael: I think it's really important for your listeners to understand how isolated medical practice historically has been within given fields. Where different subspecialists don't necessarily work together as a team historically. But innovation and science don't respect academic credentials and professional boundaries, and you frequently need to redefine those relationships in order to be successful. 

That's both from a development standpoint and a care delivery standpoint. I think that many patients really feel the benefits of that expertise when they get that multidisciplinary care. And we all become smarter doctors.

And this technology is an example of, I think, what the future of medicine is, which is being able to access the expertise of multiple different fields. And indeed, you can't do this type of treatment without it. And every day when I see how we work with our nuclear medicine colleagues, I learn something new. 

Chuck: I want to dive a little deeper on a couple of things that have come up in the last year and a half or so that you've been at the forefront of. One of them is what I'll call iterative dosing with radioligands, which is you don't go in every month and get a treatment, you don't go in every six weeks and get a treatment. You go once, and you get a treatment, and you get your second treatment when that first treatment sort of wears off, if you will. 

Is that a correct way to describe it? And, and to me that seems like a great direction forward where the patient is spending a lot less time at the doctor's office.

Michael: Yeah, I think that what we're trying to do is leverage the advantages of the imaging component, of knowing when to best treat. And again, that's not something that we can do with most medicines. We can't know, ‘Okay, what's the cancer doing and if I treat this patient now, what's the likelihood of delivering meaningful amounts of the medicine to the cancer?’

But with Theranostics, we have the ability to actually image the cancer and image the target. And by virtue of that, we should be able to more rationally dose the drugs so that we know that we're maximally benefiting the patient. As opposed to treating in a circumstance – which is quite frequent in cancer paradigms – where we do a procedure, then we give a fixed number of treatments at fixed dosing intervals, and then we're done. That's frequently done in metastatic diseases and in earlier diseases as a what we call adjuvant therapy: you have a defined procedure, then you get X amount of drug and then you're finished. We can tailor that and individualize that much more specifically using the imaging. Because we can see the cancer directly and we can see how much drug we would actually be delivering. In a lot of circumstances, we may be over-treating patients because we just are, you know, fixed in our minds that everybody gets this amount of drug.

Chuck: That's the chemotherapy idea, right. 

Michael: Yeah. But with the advantage of imaging, you can actually determine whether you're going to be effective or overtreating – or undertreating for that matter – patients by using the imaging dose to dose to determine whether or not they should continue to receive more treatment. So that is a new idea for medical oncologists to wrap their heads around.

Chuck: Yeah, for sure.

Alicia: Well, it's definitely an exciting one, because I think we all dream of a time when we can give just enough treatment to somebody to get rid of the cancer. We aren't causing unnecessary side effects because we've treated just enough, and we take care of the rest of the person and the side effects that we do cause with the treatment.

You know, that is definitely something that I see coming – and I'm hopeful actually in the relatively near future. And as we think back to your analogy in terms of taking flight and then eventually getting to the moon or, or having a space shuttle, what are your ideas? Where do we go? How do we launch the space shuttle, essentially, in radioligand therapy? As we, as we wrap up, what is your pie in the sky – or shuttle in the sky – idea about how we do that?

Michael: I think philosophically, and this applies to cancer in general, we used to have – our forefathers in oncology, whom I respect deeply – but the idea was we have to really hurt you to help you.

Chuck: Yes.

Michael: And this has been inculcated in the psychology of treating cancer. Quite a bit, even from a patient perspective. I have many patients who ask for the most aggressive therapy that they possibly can get. And while that generation did great service to you know, developing the basic precepts of cancer treatment, I think that the best therapy is the least amount of therapy that you need to receive to be rid of your disease.

And that means a focus, not so much on the number of treatments and the quantity of treatment, but the quality of the treatment. I think that my pie in the sky is: you just the right amount of treatment, upfront, early enough, so you never need any treatment again.

Chuck: Yeah. I love it. 

Alicia: I love your vision as a fellow medical oncologist. I share it wholeheartedly, and I so appreciate the time that you took to talk us through it today. Thank you, Michael.

Michael: Thank you, Alicia. Thank you, Chuck, for having me.

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Chuck:  Wow, that is so cool. I mean, what we're talking about is delivering a small dose of radiation systemically. And you know, I talk to patients about this and I say, ‘We're gonna inject a small amount of radiation into your veins.’ And sometimes I look at the patient's face when I'm explaining that because it sounds a little scary. But the whole point is because it's a low dose and because it's targeted, it's actually quite well tolerated. 

Alicia: It's really what we aim to do in cancer care. We try to get treatments that travel directly to the cancer cells, no matter how many or how few there are, but we want to get them to the level of the cell. We want to get them right there. So that even if we can't do surgery or radiation because we don't know where the cells are or there aren't enough of them for us to really perform those kinds of procedures, we can still get rid of them.

And I think that radioligand therapy offers that potential and that promise, and there are so many things that we still have to learn about it, but it's so exciting that we are on our way.

Chuck: Yeah, I mean, we're just talking about one cancer, prostate cancer, but kidney cancer, all these other cancers now they're beginning to use these treatments. So it's really going to become a new class of treatment. 

And so one can imagine in the future, we're integrating all kinds of different treatments, right? We're using immunotherapies, we're using radioligand therapies. And you can imagine that perhaps in the future, we'll, you know, do two doses of something like this. And I think that's really kind of an amazing way to think about how we're treating cancer in 2026.

Alicia: I could not agree more. Lots more good news to come.

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Chuck: Thank you for listening to the Good News About Cancer. I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. 

Alicia: And I’m Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work.

Chuck: Thanks to Lilly for support of the show. Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post-production by Alex Brouwer.

Alicia: And there's a whole lot more good news to talk about, so make sure you subscribe to this wherever you listen to your podcasts. And if you like the show, share it with someone you think might find it interesting.

Chuck: We’ll be back again soon with some more good news about cancer.