Drugging the Undruggable RAS in Pancreatic Cancer

Alicia: This is the Good News About Cancer. I’m Dr. Alicia Morgans. 

Chuck: And I’m Dr. Chuck Ryan.

Alicia: 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 before, and we're here to share that with you.

Chuck: 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.

Brian:  In terms of many of the metrics that we think about to show something might be better than what we've been doing before, this checked a lot of those – in fact really all of those – boxes to suggest that it would be better than chemotherapy. 

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Chuck: So Alicia, you know, one of the things I love about what we're doing here on The Good News About Cancer is we have an opportunity to highlight work that's really coming to the fore or reaching its culmination many, many decades after initial discoveries were made. 

Alicia: That's true. You know, there's so many things in science, and certainly in cancer, that take a lot of time from initial thought or idea to really unraveling that discovery, and certainly it takes many decades before anything ultimately makes its way into patients.

Chuck: One example of this long-term work coming to fruition is something we've talked about before on this podcast, and that's targeted therapies, which is really the result of two processes. Number one is identifying a target, which means understanding the biology of a particular cancer or set of cancers at a really, really deep level.

And then of course, the other piece is creating the way to block that target or the way to attack that target with a drug. And neither one of those are trivial endeavors, and it takes place in laboratories over many, many decades, and there are many people who have spent their entire careers working on little pieces of these types of things before they ever get put into a patient, and far ahead of the time when they would be mentioned on a podcast like this.

Alicia: That's true. Well, I think today is going to be really exciting because we're going to talk about a new targeted therapy that's giving hope to people diagnosed with pancreatic cancer. This has for a long time been what we've thought of as one of the most difficult diseases to treat, and certainly one of the most difficult diseases to live with. But this drug is changing things. 

Chuck: So we're going to talk to Dr. Brian Wolpin, and Dr. Wolpin directs the Hale Family Center for Pancreatic Cancer Research at your institution, Dana-Farber Cancer Institute. 

Alicia: That's right. Brian happens to be one of my colleagues here. Let's hear our conversation.

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Chuck: Brian Wolpin from Dana-Farber, thank you so much for joining us on The Good News About Cancer. 

There has been, I think, a sea change in your world of the treatment of pancreatic cancer, and we'll get into those details. I would love it if you could just start by telling us: what's it like being a doctor taking care of predominantly pancreatic cancer?

Brian: Well, thank you for having me. So pancreatic cancer has been a difficult disease to treat. It tends to present late, meaning the cancer has often spread already by the time it is diagnosed, and therefore it's been quite hard to cure and get rid of. 

During my first year of fellowship, a little over 20 years ago, I had taken care of several patients with pancreatic cancer. And they all were the same, and, and not in a good way. So they all presented with metastatic disease, lots of cancer through their body, and they all died within about three months. And when that happened the first time, well, you sort of figure, well, maybe that was just really a bad cancer and maybe other pancreatic cancers won't be quite so bad, and we'll do better next time.

But the next patient was the same, and then the next patient was the same, and it just became clear that we didn't know how to take care of patients with pancreatic cancer, that we didn't really have any effective therapies to do this, and that that seemed almost at the time ridiculous to me. Like, I came to Boston, to Harvard, to Dana-Farber. This is supposed to be one of the meccas of medicine. How could we not know how to do this? How could it be like this? 

And ever since then, I have studied pancreatic cancer in the lab and the clinic, and really wanted to find ways to treat patients better because they deserve to do better than what we've had so far.

Chuck: We've known for many decades that pancreatic cancer is driven by a particular mutation in a protein that has been really difficult to what we call drug. It's been difficult to treat. And this is Ras, of course. 

And if you could, just give us a little tutorial on what is Ras, what makes it such a bad thing when it's mutated, and why has it been so difficult to treat with a drug?

Brian: So Ras is present in all cells. It actually has three different forms, so sort of family members sometimes they're called, so H-Ras, N-Ras, and K-Ras. They are related to one another. They're quite similar. Some cells express one, some another. The one that matters in pancreatic cancer is predominantly K-Ras.

But the main job of these proteins is to transmit signals from the outside of the cell into the cell to the cell's nucleus to tell the cell to grow and divide. In normal cells, the cell just needs to grow and divide for a short period of time, so K-Ras turns on, or any of these Ras proteins, they turn on, send the signal, and then they turn themselves back off.

The problem in cancer – or one of the main problems in cancer – is that these genes get a mutation that trap the K-Ras gene in the on state. So now it keeps sending that signal over and over for the cell to grow and divide, and it can't turn itself off. So that's a basic reason why these genes can lead to cancer when they're mutated.

Alicia: Can you speak a little bit to the challenge around targeting this particular protein and how differentiating those K-Ras proteins that we want to turn off can be a challenge in itself? 

Brian: There are two, again, these two states of Ras, the on state and the off state. And we've known for a long time that if we could inhibit the on state, the on state is what is present at a much higher rate in cancer cells than normal cells, and also that the Ras protein, when it has a particular mutation, changes the conformation of the protein a little bit, the shape of it is a little different. And that may allow you to more specifically target a mutant form of Ras than the normal form of Ras, when normal is what's in the normal cell and the mutant form is really what's in the cancer. 

So there are a couple ways that you try to leverage your understanding of the biology of Ras to allow you to target the cancer cell over the normal cell. Part of our issue, though, has been: it's been very hard to find areas in the K-Ras protein where a drug would fit, right? So sometimes people would describe it as like a greasy balloon, which is round, and there are no crevices or things to stick a drug in, right? In order to block, usually, the function of a protein, you have to get a drug to stick into a spot where it changes the ability of that protein to signal to tell the cell to grow. 

And that also was many decades worth of work to try to find how to do that. We really didn't understand at all how to do that until about 12 years ago, 12, 13 years ago, when a chemist at University of California at San Francisco was able to find some molecules that would stick to Ras. 

And that really opened the field up substantially because once you can get one thing to stick, you can keep modifying that molecule to try to get it to function as a real drug, something you could give to a person, and that was really a big change. There have been a number of these important inflection points along the way where the field really accelerated in its ability to get to the trial, but that was one of them.

Chuck: That was Kevan Shokat at UCSF, brilliant medicinal chemist who I, uh, was proud to call a colleague several years ago when I was on faculty there, and I think just highlights the important work of medicinal chemists. As Alicia just pointed out, once we've found the target, it's not a trivial matter to create a drug to it. 

So let's move forward and, and, and talk about daraxonrasib. I think I'm pronouncing that correctly. I've practiced it a few times. Did I pronounce it wrong? 

Alicia: How, how do you say it, Brian, just so that we can get it right? 

Brian: Daraxonrasib. 

Chuck: Oh, daraxonrasib. I practiced, and you know, I'm a doctor, so I should be good at these drug names.

But, uh, anyway, it's a new drug. And sort of tell us where you got involved and how you took it from being a chemical to being a drug. 

Brian: Absolutely. I would say first to stress what you said before, that this really is a triumph of chemistry, right? This was a very hard protein to drug, and it was really collaborations between both academic labs and also industry, including biotech companies and pharmaceutical companies that have allowed us to accelerate to this point.

This drug is made by a biotech company called Revolution Medicines, who had chemists there who helped to bring the compound ultimately to the point where it could be given to a patient. So we got involved at Dana-Farber when the drug was not yet in people. 

The drug matter had been identified, and oftentimes pharmaceutical and biotechnology companies will want to collaborate with academic laboratories to test new drugs that could potentially go to people, they aren't necessarily in people yet, in the laboratory and model systems, and that can mean in cell cultures and in mouse models. Really you want to feel confident if you're gonna spend the large sum of money that's required, and to put patients at risk by giving them a new medicine, you really want to be sure, as much as you can, that in the laboratory these drugs really work. 

And so we started working with Revolution Medicines at that time. At Dana-Farber, we have a pancreatic cancer research center called the Hale Center. We have a lot of investigators here who work together, and so we had the compound in the Hale Center, and we were testing it in the lab. 

And what we saw is that the drug really worked, right? If you could use that drug to block Ras signaling in pancreatic cancers in the lab, it was very effective.

And the company Revolution Medicines had seen the same thing in their own work. And so the decision was to take that forward to what's called a first in-human study or a phase one clinical trial, where you first give the drug to patients and see how it functions. 

So we helped design that and participate in that study. We had a lot of patients that we were very grateful were willing to, you know, take this on with us. Because when we first enroll patients to these kinds of studies, we really don't know whether they will work or what side effects people may get, so it's a bit of a leap of faith from our patients to agree to do this with us, which they did.

And then from there, went to a phase two trial. Ultimately to a large phase three trial which demonstrated a benefit compared to chemotherapy. So it's been a number– quite a number of years now that we've been involved in thinking about this compound and getting it ultimately to patients. 

Alicia: When you say there was a benefit in terms of the treatment, can you tell us a little bit more about that?

Because I think it's really important as we consider how do we judge the benefit from a drug, that we explain to people and that everyone understands there are lots of different ways a drug might benefit us. It could control the cancer or stop it from growing. It could maybe even stabilize it for a period of time, even if it doesn't shrink it or change it in a negative direction, it can hold it steady.

And if it's spreading and growing, then this can still be a win, improving quality of life, reducing symptom burden, helping people have more days where they feel well, and all of these things can be signs of benefit from a treatment. And I wonder if you could share a little bit about which aspects of benefit were measured in this particular study and how this particular drug seems to actually kind of be a winner in multiple categories.

Brian: I would say to go backward a little bit to the phase one trial, the first in-human study, the first time that we really thought this drug might be working was because patients with pancreatic cancer – these were all patients who had metastatic cancer, so cancer that had spread beyond the pancreas to other areas of their body, and had all had other treatments before, mostly chemotherapy, because that's what we do mostly in pancreatic cancer – we had one of our first patients early on whose pain went away.

Because pancreatic cancer causes a lot of pain, it, it presses on some nerves that can make people have a lot of abdominal pain. And one of the things we saw is within a couple weeks of starting on the drug, the pain improved to the point that it essentially was gone, and that was really one of the first clues that this drug may be effective in people. There was obviously a, a lot of work that came after that, and that was in the phase one trial, so very early on. 

Ultimately, the drug was tested in a phase three trial, where you really can show the benefit of a new medicine compared to what we've done before. That trial was a randomized trial where half the patients got the new medicine, daraxonrasib, and half of patients could get, or did get, chemotherapy.

In that clinical trial, what we saw was that there were a number of metrics that showed benefit. Patients did live longer, so their lifespan was longer if they received daraxonrasib versus chemotherapy. The tumor was controlled for longer, meaning it took longer until the cancer ultimately grew again if they were on daraxonrasib versus chemotherapy. We also saw that the tumor shrunk more, that if you measured them on CT scans, they were smaller in the daraxonrasib arm versus chemotherapy. 

And then as you mentioned, we also evaluated quality of life, which we did with a number of different metrics, but really trying to see were people less symptomatic, did they feel better if they were on one treatment or the other, and quality of life and reduction in pain was substantially better if they received daraxonrasib than chemotherapy.

So really in, in terms of many of the metrics that we think about to show something might be better than what we've been doing before, this checked a lot of those – in fact really all of those – boxes to suggest that it would be better than chemotherapy

Alicia: You just mentioned that this is a new way to treat patients. So this is a, a sort of a new class of agents. This is a new category of medicines. And I think we are so excited about this, not only because we are helping to improve the lives of people with pancreatic cancer, but this is opening the door, perhaps, for a new way of treating cancer.

K-Ras is going to be something that could be targeted, potentially, in other cancers. Where do you see this fitting into that bigger scheme? Is this the last Ras inhibitor we're going to see? Do you think this may be something that is going to be meaningful in other cancer types and, of course, ongoing in pancreatic cancer as we look to new ways to take care of people with cancer over time?

Brian: So I think there's both the next steps for this particular drug, daraxonrasib, and then there's also many, many next steps for the field related to Ras inhibitors. There already are two other large phase three trials going on in patients with pancreatic cancer with this drug. One of them is in the first-line treatment setting, so right when people are first diagnosed with metastatic pancreatic cancer.

The trial we've been talking about has been actually in the second-line setting, so patients must have received one treatment, one chemotherapy treatment, beforehand. We think, though, that it may be better to give it earlier. So the trial that's running now is patients would receive daraxonrasib right up front as their first treatment, and that is a large phase three trial that we hope would show benefit compared to chemotherapy in that setting.

There also is a trial now that's running, which also is a phase three trial, after surgery. So we are able to do surgery in about 15-20% of patients with pancreatic cancer. But the trouble is, even when we are doing surgery, the rate of recurrence is quite high, meaning that we don't see cancer elsewhere when we take patients for surgery, but nine months or 15 months later, cancer shows up again, and the patient is not cured.

What we would like to do, obviously, is make that cure rate as high as we possibly can, and we think that using a Ras inhibitor in that setting may be able to do that. And so there's a large trial going on now to test that. 

Beyond pancreatic cancer, Ras genes are mutated in many cancer types. Pancreatic cancer's the most common – almost 95% of pancreatic cancers have a K-Ras mutation – but it actually is present in about half of colorectal cancer and about a third of lung cancer, and AML, and GYN malignancies. There are a whole host of cancers that have Ras mutations. Not always K-Ras, sometimes it's the other family members, and at a slightly lesser frequency than in pancreatic cancer, but still quite important to these other cancer types.

And so there's now trials going on in lung cancer using daraxonrasib to see if that may be beneficial for patients with lung cancer. So a lot of things going on right now. 

Alicia: I wonder if you can, as we think through kind of all of the parts of good news in, in this particular story, 'cause there are many, if you can comment on how patients can actually get good news out of participating in clinical trials.

Because in truth, this is a story again about a drug, about a protein, about a cancer, about a potential path forward for many people. But it's also a story about the success of clinical research and the patients who, as you said, selflessly engage in this, potentially going to get something out of it, and in this case, thankfully, this was a very successful trial, those patients had a win for themselves. But not every trial is successful. 

But I believe that participating in clinical research in itself can be successful. In itself, that process gives something to the patient, provides that care to the patient, and that person is actually engaging in progress even as one individual that's not necessarily a scientist or a chemist or a doctor.And it's an amazing process and an opportunity for people. 

Brian: Yes, I very much agree with you. I think we learn things from every patient we take care of, and every trial that's run we learn something from, whether the drug or the approach that we test in that trial works or not. We obviously hope it works.We do our very best to have each trial be successful, but we don't always succeed. 

There are drugs that we think will work or approaches that we think will work that don't. But I think it's incumbent on us in the medical and research fields to make sure no patient's time is ever wasted, that if they were kind enough to enroll to a trial and go on this journey with us, that we learn from their participation so that we help the patient who comes next. And I think we work very hard at that. 

I do also think, you know, these types of trials tend to run at specialized places that do a good job of taking care of patients. So I think for patients who enroll on trials, I think there also is some benefit to being at an experienced center where, you know, at Dana-Farber, we take care of a very large number of patients with pancreatic cancer, this is one of the things that we are known for. 

So if they come here, we will do a good job taking care of them regardless of how the trial either works or, or doesn't work. So I think there is some personal potential for personal benefit. There's definitely benefit to the field and the patients that come next, and sort of our responsibility is to learn and maximize what we learn and also help the patient in front of us as much as we possibly can.

Chuck: And you literally mentioned that you were working on this in the lab down the proverbial hall from the clinic as it were, and then translated that into clinical trials. And you told us about, I guess, either the mice or the cells that you were studying in the labs and the responses that you saw. But as you think about the clinical trial that you presented and the way it's making news around the world, is there one particular story that you have of a patient you treated or you know of that just stands out above the rest or is emblematic of what we hope to see with targeting Ras?

Brian: I think if we bring it back to the trials for daraxonrasib, I would go back again to that patient who we saw that their pain disappeared when they were on the phase I trial. That is so rare to see. I just-- I couldn't believe that we were seeing that. I immediately called like three people who we work with all the time in the lab and in the clinic and said, "Can you believe this?"

Including a member of Revolution Medicines who we've been working on designing the phase I trial with, and immediately, you know, texted, called and said, "You won't believe this, but here's what we just saw." And we don't see this, right? This is not something we have seen before. 

And, you know, it, it really drove us to push this forward as quickly as we could, because if you start to see the drug benefiting people, you know there are just hundreds of thousands of people out there who will have this disease who could potentially benefit. And so I think it really brought everyone together to be really focused. 

And to be honest, from phase I to phase III went about as fast as I have ever seen. The phase I trial opened in 2022, and here we are in 2026, right? And we have the results of a phase III trial, right? It just shows how dedicated everyone was to pushing this forward as fast as we possibly could.

And now we obviously hope it's gonna help a lot of people, right? From a drug that is amazing in the lab, amazing chemistry, now to being hopefully available for patients to receive. 

Alicia: Thank you so much for going through all of this with us, Brian. And congratulations to you, the investigators, and thank you so much to the patients, of course, for participating in this trial and in this success, I think the first of many.

We really appreciated talking with you today. 

Brian: Well, thank you for having me. I really appreciate it, and thank you for highlighting pancreatic cancer and advances that we're seeing.

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Alicia: What an exciting episode. This really has to be the biggest news about cancer advances in 2026. 

Chuck: I would agree, and of course you and I aren't the only judges of that. What the listeners may not know is that this was actually the lead presentation of the plenary session at ASCO, American Society of Clinical Oncology, which is the world's biggest cancer meeting, which just occurred in June in Chicago.

And Dr. Wolpin presented these data to a room full of, I don't know, 8,000 oncologists and researchers from all over the world, and he actually received a standing ovation for this presentation. And we've talked about this before, standing ovations, and how, you know, when you see that happen, it's just an electric thing because we all know that we've moved what seemed like an immovable object.

Alicia: It is a wonderful thing to see, and I think just the feeling of electricity, the, the hairs stand up on the back of your arms because you know that it's not just the people in the room that are going to be impacted, but all of those patients and their families, and the hope that is going to really come out of that single presentation is immeasurable.

Chuck: I think of all the patients and their families and how we're going to see, hopefully, greater progress, and we see patients living longer and better, and that's really wonderful. As a physician, as an oncologist myself, I have to say I think of the doctors and the caregivers, too, because pancreatic cancer has been so difficult for so many years.

And those researchers and those doctors who have focused their entire careers on this disease have probably given more bad news than any group of oncologists I think that we could assemble. And now that they are able to deliver messages of hope, I think it's really inspiring, hopefully inspiring for them.

It's certainly inspiring for me, and it's good news all around. 

Alicia: It's certainly good news, and it's definitely about time. And it's about time that we think about survivorship for these patients and for all patients, and that's what our next few episodes are going to be about. 

So thank you for listening to the Good News About Cancer. I'm Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston.

Chuck: And I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work. 

Alicia: 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. 

Chuck: 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. 

Alicia: And we'll be back again soon with some more good news about cancer.