Why Scientists Are Calling This a Pancreatic Cancer Breakthrough

[00:00:00]Hi, Dr. Shad.

[00:00:01]>> Hi, Katie.

[00:00:02]>> How are you?

[00:00:03]>> You too. Good. How are you?

[00:00:05]>> So, I'm I'm well, thank you. I'm so grateful that you're joining us. First of all, I'd like to say congratulations.

[00:00:14]Um, what has it been like for you to get so much attention for this new drug that you really have developed uh for the treatment of pancreatic cancer?

[00:00:26]Well, I I mean, I think everybody at Revolution Medicines, the company I'm involved in, really deserves the the the real credit. They really discovered this amazing molecule, kept on the uh the trial to get the dose right, which we might get to, and and really uh get an outsized response much better than we expected. So, um, it's been usually in cancer therapies, we get a little bit or a lot of disappointment, and this is one of those that, uh, really flip the other way and in such a such an important cancer. Uh, so it's something I think everybody in the cancer community and those focused on Kass uh, have been waiting for for honestly four decades.

[00:01:12]>> Wow. Well, it's so it's it's so exciting. And I want to before we talk about the approach that seems to have extended life um not long enough for me in my view. We can talk about that in a moment. But can we first talk about why pancreatic cancer is so notoriously difficult to treat and why the survival rate the 5-year survival rate is so low.

[00:01:39]>> Yeah. Yeah. I mean I think it's largely for two reasons. First is it's detected very late. It's the symptoms don't uh present themselves to people to know they've uh got the cancer. So we detect it very late. And the treatment side, it's a cancer that's caused by mostly one mutation in one gene called Kass.

[00:02:04]And that gene codes for a protein that we just didn't have a drug for. So, we didn't have a way to take a pill that would shut off that protein. And that's what kind of held it back for three decades. And that's kind of what my lab works on. And once we got some traction, then now it's been an explosion. And now we see this clinical benefit. So now it's going to be even more of a of a, you know, focus for everybody.

[00:02:35]>> Ah, I'm sure. My sister Emily died of pancreatic cancer about 25 years ago and uh it was obviously a brutal experience for all of us and so I in particular and I of course I know other people who have succumbed to this disease in the years since. So this is particularly meaningful for me. Um, and and I and I also think one of the most exciting things about this new approach that you all have have really um worked on is the efficacy it could potentially have in other cancers. But I really want you to dumb it down for me first because I feel like I know a lot about cancer, but I still am a little confused about >> KASH role it plays in pancreatic cancer in particular. and then we'll talk about other cancers as well.

[00:03:29]>> Yeah. So, you know, Kass has a a really kind of outsized role in our understanding of cancer. It was found to be the first human anka gene. And this is at the time when people thought, oh, a lot of cancer is caused by viruses maybe because we studied them in tumor viruses. That's where we understood the genes. But then in 1982, four labs simultaneously found mutations in the gene in human tumor cells. So that all of a sudden flipped it to say, oh, cancer mostly isn't caused by viruses.

[00:04:06]It's actually by these mutations. And then over the next decade, we realized the most common mutation in a driver is in Kass. That's a third of all cancer is because of this gene, this one mutation.

[00:04:23]It's unbelievable really.

[00:04:25]>> So, so can you explain what the K RAS mutation is like for a fifth grader?

[00:04:32]>> Yeah. Yeah. Yeah. So, the the the one thing about cancer that that that is that we get these mutations that turns the protein on. It locks it into the on form. Normally without the mutation or the wild type form that we have, it goes on and off and on and off and it usually just goes on for a second and then goes back off cuz it's telling your cells grow a little bit but then don't grow too much. But if you get the mutation, it's stuck on and then it's grow grow and that's gives you the potential for the cancer.

[00:05:10]So it's we call it a molecular switch and it the mutant switches it on. Yeah.

[00:05:16]>> So so is this drug and you can pronounce it for me. Can you please come up with a with an easier drug pronunciation for me please?

[00:05:27]>> They all have very funny pronunciations.

[00:05:29]Yeah. But but this drug that you developed, it turns the K Rass the mutation off and says stop stops with the cellular division and and kind of gets it to to stop multiplying. Is that right? Or dividing.

[00:05:46]>> Exactly. Exactly. Cuz and and I should say I I didn't develop this drug. This was really developed at the company that I'm a co-founder of. But we worked on a previous drug for K RAS and I can explain that that that really opened up the door to this drug and the way that the molecule does is it binds to the active form and it just turns it off and now cancer cells they've become addicted to this on form of the protein. So when we take that away they die.

[00:06:20]That's the essence of targeted therapy for cancer that the cancer cell uses something that our normal cell uses but it sort of switches it all the way on and then its survival is dependent upon that on switch and if we can take that on switch away then the cell dies and that's kind of the basis. Yeah.

[00:06:42]>> Which is so exciting. So the survival rate in these clinical trials for the people who were on this specific drug that your company developed it it it went from what something like 5 months to 13 months. Is that right?

[00:06:57]>> Yeah. A little more than 6 months to 13 months. Exactly. Exactly. So what so which is so exciting but honestly if I had somebody or if I had pancreatic cancer I would be grateful for increasing the survival rate but is only just slightly over a year. What happens what happened to the patients who were using this drug obviously it stopped working right? Yes. And part of that is we think we need a better drug earlier so that we get more of the cells to die.

[00:07:32]And then we're going to learn now from this how to make a better drug so that when the cells evolve, the ones that didn't die, when those evolve to become resistant, we can come back with another drug and hit those. So in in other cancers, that's a typical thing we've seen. And we've seen some 3 months, 6 months overall survival. And then we make better and better drugs. We know the target is right. We know the drug works, but we can always do better on chemistry. And then survival gets out past 5 years. So I'm not saying that we're around the corner from that, but the actual, you know, sort of understanding from this successful trial will really inform the next drug and the next drug. Well, I was going to ask you where are you in the development of drugs that will come in once a patient becomes resistant to the one that seems to have ex extended life uh by a matter of of several months.

[00:08:33]>> Yeah, there there are probably 50 other drugs targeting the same protein in clinical trials now. It's mindboggling how many drugs are being, you know, developed now. And I'd say that's important because we know the resistance most frequently to these drugs is the cell turns up the RAS even more. It makes copies of the gene so that it can have more of the protein. But we have ways to get rid of the pro other you know the whole community. I mean we have ways to get rid of the protein. We have ways to clamp and hold on to it even tighter. And so we think that once the cell gets this KAS mutant, it's addicted and stays addicted and that means the chemistry can be more and more focused on the pathway.

[00:09:24]>> And that's that's really I think just, you know, it's great that the bar is raised, but like you said, we got to get much higher than that bar.

[00:09:34]>> Cancer is just so diabolically clever, isn't it? How it can outwit, you know, these medications. But you're saying there's a whole class of medications that can now come in and basically turn these systems off. And if one finds a way to kind of get around a particular drug, what you're hoping is there will be this whole class of drugs that will then be able to come in and attack the cancer that the patient isn't resistant to, is more receptive to. Is that is that accurate?

[00:10:11]>> The last part is not so it it the last part you're getting at a really interesting question about whether we're driving it towards evolving a place where it's sort of in some map it's a dead end and we can really quench it.

[00:10:25]People are trying that. We don't know if that will work but we do know once it becomes resistant we know the next drug to try and to try and to try. Yeah.

[00:10:35]Let's talk about what this discovery means for other cancers. Are there particular cancers that this may be useful in this this new targeted approach that you've figured out?

[00:10:49]>> Yeah. Yeah. So, you know, the we we talked a little bit about how Krass is the third most common cause. It's involved in a third of all cancer, but it's in three main subtypes. Pancreas it's about 90%. Colon cancer it's about half and in lung cancer it's about a third. So these are big cancers as we all know and Kass is a big part of each of those. It just happens to be almost all pancreatic and it's half of colon and a third of lung. So this drug is getting tested in each of those. We already have two drugs approved in lung cancer for Krass. That's the one I was mostly involved in and that is already showing better and better efficacy with the next drugs that are in phase three and getting tried. So each one of these Kass driven diseases are going to be treatable. We already have approved lung cancer drug and approved colon cancer drug. Now this one hopefully will be pancreas and then there's lots of variants of them that we're going to see drugs for. And and and so what percentage of lung cancer are kass?

[00:12:02]>> About a third.

[00:12:03]>> A third. And for those half of colarctal cancers and 2/3 of lung cancer >> or oneird one >> no the the two >> the remaining sorry >> do we have idea what sort of genetic mutations are causing those or those a whole host of of them >> there? We actually do know about the the non-krass ones and those in lung are EGFR. There's um inhibitors of EGFR that are antibodies that like satuximab and then there's small molecules like osimertinip. Those are breakthroughs for for lung cancer. For colon cancer, we have BFF and other kynise and we have approved drugs there. And we're seeing in colon it now we're talking about the three different uh tissues. It's it's it looks like when we make a drug for K RAS and we put it into lung, colon or pancreas, lung patients respond the best, then pancreatic cancer then colon.

[00:13:10]So colon seems the hardest to try to you know make one drug work. But in colon cancer, we see now that two drugs together will make them respond like a lung cancer. So we're really on the brink of of seeing how to get these drugs combined and make them work even when the tissue that the tumor is in is not as sensitive. Yeah.

[00:13:35]>> By the way, I just want to encourage anyone who's watching if they have any questions or if they know anyone. Um, I guess the question is, um, you know, when I talked to Allison Ocean about this, she's a friend of mine who's an oncologist at New York Hospital. Um, and we were talking about Ben Sass and the the side of, >> you know, Senator Sass, uh, I guess was on this drug, right? And he had just terrible, terrible uh, painful soores all over his face.

[00:14:05]I'm sure you saw that.

[00:14:07]>> Maybe you're even involved in his treatment. What about some of the side effects? She said that some of that would go away, but can you just address that?

[00:14:17]>> Yeah. Yeah. This is a great uh this is a big big kind of issue right now. And really, you know, we we talked about the mutants of Krass, right, that cause the cancer. And what we in my lab made was a drug that was mutant specific for a a kind that comes in lung cancer. So that drug only binds to the mutant and only turns off the cancer cell and not the rest of the body. So that drug is approved. There are two of them and it does not have the rash. Now when we go to durax on rasib and talk about it, it binds to all the forms of ras wild type in the rest of our body skin and in the tumor. So we kind of we expected this to be a toxicity because we've seen it in other drugs that are inhibiting in normal cells as well as the tumor. So what we're thinking of and I think what are coming in now are more of the mutant specific drugs. So they will overcome a lot of that toxicity because they'll be more targeted to the tumor cell. So this one is still on on balance a a big step but I think in the not too distant future we should be able to see much better tolerated uh with without these uh toxic side effects because of the ability to go after just the cancer mutant in the cells. So do you think this is going to be widely used for people you know like uh a firstline treatment for people who say are diagnosed with pancreatic cancer?

[00:15:59]>> Yeah. I mean I I should step back and I I'm a PhD so I my chemistry so I we do the chemistry not an MD but I we the company does have a trial in first line uh with the drug and I I think when this overall survival benefit is actually even longer than what first line patients see we can imagine it will go go to the first line so I I think that's a reasonable expectation >> and this may not be in your area of expertise either Dr. showcap. But obviously diagnosing pancreatic cancer earlier before it has metastasized to like the liver or the lung, the brain, you know, other organs is really critical and um you know ideal because when cancers are diagnosed early, they're much more treatable and curable. you know, um I'm sure probably this isn't within your area of expertise, but do you think we're making any progress in in our ability to diagnose pancreatic cancer in particular, which is so so deadly, earlier so it can be treated perhaps with this new drug?

[00:17:15]>> Yeah. Right.

[00:17:16]>> No, you make a fantastic point and I and I think the motivation to get that early diagnosis and and detection piece, right, is even sort of more motivated by this drug because before we really didn't have a drug to give patients. So now that we know there is something, I think there's a lot of motivation. A lot of the foundations like the Lust Garden Foundation and this new Stevenson Foundation that I'm involved in are really putting a lot of funding into into that and I know Standup to Cancer that's a very very large uh effort and um and I think that's all those you know discoveries that yet to come are in the right place. That's where we should focus.

[00:18:02]>> Well, it's really exciting. What was it like when you were at ASCO when you got that standing ovation? That must have been moving for you as uh as a scientist.

[00:18:13]>> Yeah, I actually wasn't there. I had a lot of people sending me videos and pictures and so I I got it sort of secondhand, but they told me over and over how amazing it was to be there. And uh like I said, we were just on pins and needles up until about 6 weeks ago waiting for the trial to read out. So, >> well, as somebody who's um whose life has been so affected by cancer and uh as a co-founder of Standup to Cancer, I can't thank you enough for your work and how meaningful it is for so many people uh and the fact that you're giving a lot of people hope uh for better treatments uh is just a phenomenal thing. And I'm just I I think I speak on behalf of everybody watching this how grateful we are to your work. I often say that scientists are really the unsung heroes of our society and it's just so wonderful for me to be able to express my gratitude to you and all your colleagues. I know that it takes a village that you didn't do this alone that you worked with another scientist for Is there any Greg Verdine from Harvard to develop this molecular glue I guess that helped adhere to the cell.

[00:19:34]Right.

[00:19:35]>> That's right. Right. We didn't even get to talk about exactly how the molecule works, but it's a >> Go ahead. Why don't you you can talk about tell us.

[00:19:42]>> Yeah. Yeah. This this molecule is fascinating. It's kind of based on how we learned 40 years ago how natural products work that one of the famous ones is rapamy and it it binds to one protein in the cell and then that binds that complex binds to another protein.

[00:20:01]So the molecule is in the middle of two proteins and it's a molecular glue. And what uh Greg's company Warp Drive started and what Revolution Medicines finished was turning that into a designer molecular glue so that it would go after not what evolution gave us but what we want for a treatment for pancreatic cancer. And there's a lot of development in that in the whole you know chemistry field. We're just seeing so much new creativity and chemistry to go after hard to treat targets. We've had this word that we refer to things as undruggable and KAS was the pinnacle of that and once we started sort of changing that it really motivated a lot which is great for the patients. It's it it's it's it's so exciting. And um you know I I wish I were a scientist because I sort of understand a lot of the chemistry. I always sucked at chemistry.

[00:21:00]Um so I try to kind of visualize what you're talking about um as best I can.

[00:21:07]But um just again, thank you to all your colleagues. Thank you to you uh for for working so hard to develop this and to have this new approach. And this is especially important at a time where federal funding >> has really declined and supporting scientists like you and academic centers. Um how how how >> how much of an impact has that had on your work or is it not that impactful because you're a private company?

[00:21:39]Yeah. So the revolution medicines it hasn't but I mean my laboratory is at the University of California San Francisco and so we're funded by the Howard Hughes Medical Institute which is a private and that's sort of a more blanket funding but all of my colleagues I think are under pressure and shutting down their labs reducing the size and and it's it's just a shame because we see the moment we're in of so much potential that it really uh is is sort of cutting out uh our legs from under us right when we're beginning to run and uh it it's it's a real shame. So stand up to cancer is one of those bright spots.

[00:22:20]So I really we we got early funding for our early drug and lung cancer from the standup to cancer. So I want to thank you for all you've done for that.

[00:22:28]>> Oh absolutely. Well Dr. Kavon Shat, am I pronouncing your name correctly way?

[00:22:34]>> Perfect.

[00:22:34]>> Dr. Thank you again for spending time with us. Please keep us posted on any other developments. And um it's just wonderful, as I said, to be able to spotlight a real bright spot in in cancer research, especially during some of these very difficult time for a lot of your fellow scientists. So again, thank you for for explaining it and thank you for being with us today.

[00:23:01]>> Thank you for having me on.

[00:23:02]>> Okay, take care. Nice to meet you.

[00:23:05]>> Yeah, nice to meet you.

[00:23:06]Anyway, that wraps it up for us. Dr. Showcat was uh thank you for for being able to figure out Substack as well. And we'll be back. Uh I don't think I'm going to be able to do this next week because I'm going to be at the Aspen Ideas Festival, but we'll be back in two weeks. And um thank you all so much for joining us as always. And what a great way to end this conversation. Thank you again, Dr. Shoat.

[00:23:31]>> Bye-bye. Okay, bye everyone.