Repairing Cancer Cells Rather than Destroying Them

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one and sarcoma programs. Today I'm happy to be joined by, Dr. Yogen Saunthararajah, a hematologist in the department of translational hematology and oncology research. He's here today to talk to us about a novel way to treat cancer by repairing cancer cells, rather than destroying them. So welcome, Yogen.

Yogen Saunthararajah, MD: Thank you, Dale. I'm very happy to be here.

Dale Shepard, MD, PhD: Good to see you. Glad you're here. Maybe you can start off, give us a little idea, what's your role here at Cleveland Clinic? What do you do?

Yogen Saunthararajah, MD: So I'm a practicing hematologist oncologist, Dale. I see patients with blood diseases in the clinic, but I also run an NIH-sponsored laboratory, where we do research into trying to understand how cancers come to be, and trying to use that understanding to develop better treatments for cancers and also some other important blood diseases.

Dale Shepard, MD, PhD: Okay. So we're going to focus today on this whole concept of repairing cancer cells. It's something you don't think about all the time.

Yogen Saunthararajah, MD: Right.

Dale Shepard, MD, PhD: Tell us a little bit about what that means.

Yogen Saunthararajah, MD: Yeah. So, Dale, if we step out for a moment and look at the landscape of medicine, right, rheumatology, pulmonary allergy, oncology. It's only in oncology really that we have this search and destroy mindset and paradigm. And the reason we have that mindset is because the diseases we deal with, i.e. cancers, we really didn't understand for decades upon decades exactly how they came to be a cancer, right? So if you don't understand what the machine is, how can you even think about fixing it? So it was bad and we didn't understand it so we defaulted to search and destroy so it was very crude, and that's reflected in how things pan out in the clinic, right? The treatments can be pretty brutal. They can be tough, and they often, too often do not work very well.

So we don't do this in asthma, right? We don't say, "Hey, you've got asthma. You need a lung transplant." Right? We say, "Well, those tubes are narrow. Let's understand why the tubes are narrow and let's fix it. Let's make those tubes wide again." We really need to be doing that in cancer. We need to move away from search and destroy to, "Hey, well, why have things gone wrong? Why is there this cancer? And how are we going to fix it?" I would just point out conceptually an important detail here. The cancer is not an invader like asthma, like rheumatoid arthritis, like diabetes. It's ourselves gone wrong. It's not an invasion by something foreign or something alien. It is us. So we do need to understand how we went wrong so that we can fix ourselves rather than destroy ourselves.

Dale Shepard, MD, PhD: I guess an extreme example of that, trying to just eliminate everything would be in the past so we did transplants for breast cancer.

Yogen Saunthararajah, MD: Yeah.

Dale Shepard, MD, PhD: The thought was that we just didn't give quite enough chemo, and if only we could give more.

Yogen Saunthararajah, MD: Yes, more search and destroy, right?

Dale Shepard, MD, PhD: Right.

Yogen Saunthararajah, MD: "Hey, not enough search and destroy. Let's get more search and destroy." 'The old destroying the village to save it mistake.'

Dale Shepard, MD, PhD: Yeah, it's an interesting concept. I oftentimes have discussions with patients that their expectation is that I eliminate all of their cancer.

Yogen Saunthararajah, MD: Yeah.

Dale Shepard, MD, PhD: Yet they've had diabetes or hypertension for 20 or 30 years, and have never once asked, "Why isn't this cured?"

Yogen Saunthararajah, MD: Right.

Dale Shepard, MD, PhD: So it is a different mindset.

Yogen Saunthararajah, MD: Yeah, right. There's these mindsets, these ingrained habits of thinking that then even subconsciously set the agenda for all that follows. And these agendas are massive agendas, multibillion dollar research agendas, treatment agendas. So sometimes we need to step out and just examine some of these assumptions that underlie how we think about problems. This applies very much in the world of cancer. Yeah.

Dale Shepard, MD, PhD: So, how do we move toward repairing cells? What does that mean? Tell us a little bit about what you're trying to accomplish.

Yogen Saunthararajah, MD: Yeah, so of course we need science, right? So we need to understand what is the cancer. And again, let's step out and take a big picture view, a view of the essentials or the fundamentals before we drown ourselves in details, right? The big picture is; what is cancer? A high school student could tell us, right? If we asked a high schooler, they'd say, "Oh, okay. Cancer, it's cells that just keep on growing and growing, and they BA basically don't stop." Right? That's what it is. And that actually is what cancer is. Now, let's delve into that a little bit more. Cells growing and growing is actually entirely normal. In fact, it's essential. That's how we stay alive, right? To be alive is to replenish and regenerate continuously. And so every day we actually have billions of cells in our bodies that grow and grow.

They have to do that just to maintain our skin and our gut, and our own marrows and everything, our brains, everywhere. The difference though is that in cancer, that process doesn't stop, right? So it's actually to refine the understanding, it's not a problem of growing and growing. It's a problem of not stopping because the growing is normal. And really once you realize that, it opens up a lot of scientific doors towards understanding what is the essential engine or foundation for carcinogenesis, for cancers coming to be.

Dale Shepard, MD, PhD: Have you come up with any good targets yet? Tell us a little bit about the research you've done and some potential targets.

Yogen Saunthararajah, MD: Right, yeah. So as I just alluded to, the problem is not stopping, right? And the main reason that those billions of cells in our bodies stop growing and growing is because they arrive at their final destination. So the reason they're growing and growing is so that they can replenish all the specialized cells that keep us alive, right? So the specialized skin lining cells, gut lining cells, the white cells that fight infections, the red cells that carry oxygen, the glial cells that maintain our nerve cells and our brain cells. So they grow and grow. Each time they divide, they morph a little until finally they make the specialized cells that we need to be who we are. So cancer is a failure of that journey to proceed to completion. And this, we can actually see, very simply we can just look at a cancer under the microscope and we can actually see that.

We can see a breast cancer is breast cells that have failed to complete the journey to making a cell that makes milk. A brain cancer is cells that fail to complete the journey to make the glial cells that support the nerve cells that help us think et cetera. So once you know that, you can actually focus on the machinery that enables that journey, right? So how is it that that a cell that wants to become a white cell to find infection, how does it actually get there? And it turns out that to get there, the cell has to do a lot of unpackaging work. It has to unpackage all the genes that define what it is to be a white cell that fights infection.

Those genes are actually packaged away because all the cells in our body are on different journeys, right? Some cells want to be a kidney cells. Some cells want to be a white cell that fights infection. And these different types of genes are actually packaged the away neatly to avoid confusion. But it does mean therefore that the cell that is on that particular journey needs to do work to unpackage. It has to untie the ribbons and remove the wrapping paper, take the stuff out of the box. Each one of those actions requires certain enzymes. And what cancers do is almost universally, actually universally one way or the other, they impact the function of that sort of machinery, that sort of enzyme machinery.

Now like everything in life, you have enzymes or machines that do one thing, and then you have enzymes or machines that do the opposite, right? To maintain balance, yin yang, positive, negative, as in much of the cosmos, so in us, right? So you have these opposing groups of enzymes. So cancers get rid of these enzymes, that unpackaged genes to complete journeys, to specialize cell fats. And they will simultaneously actually select in the process of evolution to become a meaner cancer, they will select to amplify or gain and function of the enzymes that do the opposite, the stuff that keeps the genes packaged away in boxes that the genes to be the specialized white cell, et cetera.

So those guys, that latter set of characters, the fellows that actually are amplified, they gain in cancer. Those are the targets. So you have loss of function in one whole category of family of machines. It's really hard technically to replace big machines that are missing, right? It's just technically not very feasible to have a pill that's going to go all around the body and replace big chunks of machinery. But it is relatively simple to break the guys that now have a gain of function that have unbalanced activity. You can get small molecules that will go in there and interfere with that opposing set of machines. Those are the targets for therapy that allow us to fix. So I hope I didn't lose you there.

Dale Shepard, MD, PhD: No.

Yogen Saunthararajah, MD: Basically there's an imbalance in two different types of forces, that imbalance is created genetically. And what we do is, we come along with drugs to rebalance the system, not by replacing missing pieces, but by interdicting the fellows that now are overactive.

Dale Shepard, MD, PhD: Now, are there particular types of cancer you think will be best suited for this kind of treatment? Do you think hematologic malignancies where there's more clonality compared to solid tumors where there may be more heterogeneous ways that they became cancers and response rates, or maybe would suggest that there's more variability? So any types of cancers that you think might be better suited?

Yogen Saunthararajah, MD: Right. Great question. There's actually two levels at which we can answer that question, right? So one level is, "Hey, this sort of model that you just proposed; Yogen for yin yang imbalance, does it apply broadly in all cancers? Does it only apply in some cancers versus others?" To answer that question, actually now with the genomics revolution, not that difficult, we can actually look at cancer genetics, and in cancer genetics it's universal. So any cancer, all cancer demonstrates this specific imbalance that amongst the genes that are most recurrently physically removed from cancers, are genes for these machines that unpackage the genes needed to become something specialized, to become that white cell, to become that skin cell, to become that glial cell, to become that kidney cell. So basically the basic science is telling us that this is how everything is broke, whatever the cancer, this is how it's broke.

This is a fundamental element in how cancers come to be cancers. Of course, there's lots of other stuff going on, right? It's evolution, there are all sorts of other, but this is fundamental. Just the frequency with which this machinery is just black and white destroyed, ejected from cancer cells, says this to us. So that's one level of answering your question. Now, the next level is, "Hey, you've got a drug, a small molecule that somebody can eat." And the goal, the dream is that it's going to get into the cancer to fix the guys that now have unopposed action, right? The fellows who are because of their unbalanced activity are driving the cancer phenotype. And that's actually easier to do for liquid cancers. Liquid cancers are floating around, and because they aren't sitting in place with a fixed blood supply and a fixed structure around them, they're hungry.

They eat stuff that's in their environment, and that will include our drugs. So that's a big element of why with some drugs, they work better for treating blood cancers, the kinds of cancers that I see in my clinic versus the kinds of cancers you see in your clinic. So the answer there is, the science tells us that it operates both your cancers and my cancers, but we need better drugs, basically. We need to understand what are the impediments to getting the putative solutions, right? The scientifically sensible fixes, but then we need drug science.

So basically there's a whole arena and world of science that's focused on understanding the genetics and the biochemistry of a cancer cell. There's a whole nother world of science, and that's centered around understanding how a drug, how it gets into the body, how it moves around the body, which tissues is able to penetrate, how long it stays in any particular type of cell. That's a whole different world of science related to drug metabolism and transporters, and all sorts of other stuff, and we need to also master that so as if we needed another layer of complexity but really-

Dale Shepard, MD, PhD: We really did.

Yogen Saunthararajah, MD: You need to address, you need to do both if you actually are going to take that science and turn it into better treatments for patients.

Dale Shepard, MD, PhD: So I guess from a thinking about a solid tumor as you mentioned before about their fixed blood supplies, are we thinking that if someone's identified to have a cancer, that maybe the approach would be some element of traditional treatment to get rid of what's there, but some element of a newer type of treatment to prevent further growth? And so maybe something to block growth, but also to get rid of what might be present or?

Yogen Saunthararajah, MD: Yeah, in so far as our traditional treatments do have activity, of course, I think that makes sense. I'll be honest, okay? My dream what keeps me up at night, and wakes me up in the morning after a fitful rest, is I want a world where we have five drugs that all fix and non destroy. So nobody's hair is falling out, nobody's throwing up, where there's no pictures of kids with bald heads and having to wear a scarf. You know what I mean? I want us to get to that world. I believe the science is telling us that world is possible. Actually, to give you my frank opinion, Dale, I think we have the science already. It's the drug science where we are way behind, it's the drug science aspect here.

I think the actual genetic science and the biochemical science, it's hard to argue with. It's the genetics. We have 10s of 1000s of genomes of cancers, and we can just see what's what, and we need to just see that clearly, it's there for everyone. You can just go online and you can gaze upon it. The hard part is, we need to devote the drugs. It's too easy to say, "Hey, you know what? I just want stuff that's going to damage cancer cells and destroy them," right? It's actually not that hard in terms of, "Hey, do you want to feel happy that you've done something productive? You can take cancer cells in your drug company laboratory, and you can add anything, almost anything, and you'll kill them.

And you say, "Hey, I'm killing cancer." The challenge is we can't kill the patients. We have to... The challenge is to get the bad guys and not the good guys. And for that, you need precision. You need to have the right targets. You ask me, "What are the targets?" You need to have the right targets that when you engage those targets, the cancer relies on them, but normal cells don't. These unbalanced enzymes that I just talked about, they are in that category because when you engage those targets in a normal cell, a normal cell is already on the journey to becoming specialized white cell or specialized kidney cell or whatever. So when you engage those targets that enable genes beyond unpackaged, they just unpackaged stuff they were going to unpackage anyway.

It's in the cancer cell where they're relying and dependent on these enzyme targets to prevent the unpackaging of the genes that would complete their journey, right, would take them to the Terminus and they would stop traveling. They don't want to do that because they want to keep on growing. That's their evolutionary drive. But if you inhibit these enzyme, they complete the journey. So it gets the cancer. The cancer is predicated on this defect, but it doesn't damage normal cells. So long as your drugs are specific and you're dosing them right, and all of that. So it's the drug science. Shockingly they'll, today, as we sit here, I can think of only three drugs on planet earth that have the ability to engage these targets that we're talking about without doing stuff that we don't want. And there's only three molecules on earth that's not cost-

Dale Shepard, MD, PhD: That sounds like a big gap.

Yogen Saunthararajah, MD: That's a big gap, man. We have 100s of molecules that the goal of which is to damage stuff, right? "Hey, damage the DNA, damage the RNA, damage the proteins, damage the membranes, damage the cytoskeleton plus radiation." Hundreds, but we have just three molecules that a human being can take in the clinic, and they have the possibility of operating in the manner that I just talked about. And all of those three molecules have profound pharmacology limitations. They're scientifically sound in terms of the targets they engage, the effects they can produce. But because of how they are absorbed and distributed in a human body or a mouse body for that matter, they don't get into most cancers. They get into some and they have critical roles for treating some cancers, but they just don't get into most cancer cells.

Dale Shepard, MD, PhD: How do we change the paradigm? How do we make a shift? You're absolutely right, we-

Yogen Saunthararajah, MD: Data. So the great thing about science is, it's conservative, but necessarily so, but it yields to data, and that's why we publish, right? That's why we put in years and years of work and go through all that painful peer review and the rejections, blah, blah, is to eventually get the data out there.

Dale Shepard, MD, PhD: Yeah.

Yogen Saunthararajah, MD: And with time, with years, more and more people recognize the data. Ultimately the most important data is clinical trial data, right? So is to get the science to the point where you can have a new drug that goes into the clinic and actually does save lives without hair falling out and throwing up and all that stuff. And then people will really begin to notice. So we just need to stay in the game and persevere and generate data, and we will get there.

Dale Shepard, MD, PhD: If you had your crystal ball, how long until we have such a drug?

Yogen Saunthararajah, MD: I don't think it's going to be that long, Dale. I'd say five years. We're going to have more. We actually already have, when I said there are three drugs, I was really thinking about drugs that in theory should be effective broadly in against cancers. There's actually a few others that work in this paradigm, so this repair paradigm. But for very narrow subtypes of cancers defined by very specific genetic abnormalities. A famous one is a type of leukemia that has a translocation of the retinoic acid receptor. We have two drugs there. They produce a 95% cure rate, okay? That's how powerful this underlying science of biology is. But they only work in that particular leukemia for biochemical reasons. So we basically need drugs in that paradigm but which work broadly, engage very broadly, the specific enzymes that all these cancers are relying on to prevent them completing their journeys to being something specialized. We're going to get there, five years, okay?

Dale Shepard, MD, PhD: All right, five years.

Yogen Saunthararajah, MD: But check in with me in a half years.

Dale Shepard, MD, PhD: I will have you back here in five years.

Yogen Saunthararajah, MD: Yeah, maybe once a year.

Dale Shepard, MD, PhD: We'll talk all about it.

Yogen Saunthararajah, MD: I'll give you progress reports. I'm having so much fun, you have to bring me back once.

Dale Shepard, MD, PhD: There you go. Well, it's great that people like yourself thinking of really novel ways to treat cancers. Keep up the passion, the good work, and we'll have you back at five years to talk all about it.

Yogen Saunthararajah, MD: Okay, Dale.

Dale Shepard, MD, PhD: All right. Thank you.

Yogen Saunthararajah, MD: Thank you much.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation, once the appointment is scheduled.

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