[0:00:00] Dr. Diane: We talk about battling cancer, but it's the most diabolical and ingenious foe. Today we'll get to know the enemy and understand its genesis a little better. Let's get started.
Hello, I'm Dr. Diane Reidy- Lagunes from Memorial Sloan Kettering Cancer Center, and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have straightforward, evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier, healthier lives. For more information about the topics discussed here or to send your questions, please visit us at mskcc.org/podcast. I'm here today with my dear colleague and friend Dr. Juan Ma Schvartzman, an oncologist at Memorial Sloan Kettering Cancer Center. He's also a scientist in the laboratory of our CEO Dr. Craig Thompson, which is part of our Cancer Biology and Genetics Program. As a physician scientist, Juan Ma is uniquely qualified to walk us through how this villain develops. Juan Ma, it's a delight to have you. I'd like to start the podcast with the basics. What is cancer? And why does it develop?
[0:01:14] Dr. Juan Ma: Well, again, thank you for the invitation. I'll do my best to answer, it was probably the hardest -- well, one of the hardest questions. I think one of the things that's most difficult for us doctors to explain to patients is that cancer is just an amalgamation - a group of many, many different diseases. It's sort of like saying an infection. And so when we talk about things, well, how do you treat cancer or how do you cure cancer; you really have to get into the specifics of what is the type of cancer that we're talking about. I think the one common thing that everyone for sure agrees on is that cancer is a disease in which cells divide or grow uncontrollably when they shouldn't. There are situations in the body when cells proliferate very quickly, but it's always regulated and it's always due to a particular reason. But I think that's where the commonalities to all cancers kind of stop. And the more that you add specific things, specific caveats or processes, the more that you'll restrict, there'll be examples of cancers that don't meet those criteria. So for example, if you just limit it to dividing uncontrollably. I think the first division we all kind of acknowledge is that tumors that arise in the blood essentially, are leukemias, and some people will include lymphomas here as well, are very different from tumors that arise in solid tumors [indiscernible] [00:02:36]. And that's because one of the things that we think about in cancer is that the cells not only grow in the place where they started to grow, but they can start to become invasive, and I think that's a commonality of cancer. But the blood cells, let's say, have the ability to travel anywhere they want normally, and so they don't need to acquire that. So not only do they need to grow uncontrollably, they need to be able to invade either locally or to other parts of the body. I think that's as broad a definition you can give, I think the moment you start giving more specifics, you lose many different types of tumors.
[0:03:13] Dr. Diane: Absolutely. And I think historically, as you said, and because of that, people knew for centuries that there was badness with these cells, but they didn't know why. But yet some how along the way there were lots of brilliant scientists that came across the idea of the genes of these cells somehow go awry. So the genetics, what you study every day, seem to be the culprit. It used to be viruses, it used to be black bile, it used to be all these different sort of concepts and theories as to how these cells figured out to get to places where they shouldn't be. But there was sort of this revolution if you will, that somehow these genes that were responsible for these different molecular cascades and pathways etcetera, are the culprit and getting damaged or gone awry were responsible. Is that fair to say?
[0:04:06] Dr. Juan Ma: I think that's true. I think a lot of what we've learned, I guess the second half of-of the 20th Century is that cancer is definitely a genetic disease. It's interesting that you mentioned viruses, because a lot of what we learned about the type of genes that drive cancer, we learned through studies by Harold Varmus, who used to be here about how viruses cause cancer. And a lot of that is through mutations in our normal genes. And I think this kind of gets at the idea of what drives a tumor, you know, why do these cells that are presumably normal start dividing uncontrollably. And I think the easiest way to think about it is that there are all cells -- most of the cells in our body are really committed to being very, very specialized, but there are subsets of cells that retain the ability to divide, but they normally don't do so, and they only do so when they get the signal to divide. So some signal tells the cell in the colon to divide or in the bone marrow. And-and -- and so we, in the kind of very basic way, in cancer biology or genetics, we think that there are some genes that are responsible for the code to make a protein that can be thought of as a gas pedal, and then there are other genes that are like brakes. And so when you classify many of the cancer mutations that you see in patients, you can see that there are some mutations that make gas pedals be permanently stuck. And so that cell that has that mutation, is getting a signal constantly to divide, divide, divide, divide, even though there's no signal from the outside. It's just it has this gas pedal that it can release, and at the same time, there are breaks that would normally when a cell is dividing, say, “No don't divide so much. Stop dividing,” and those brakes can be broken. And so that's a very useful way of classifying most of the genes that we associate with cancer.
[0:06:09] Dr. Diane: So just to reiterate, we're talking about genes in the cell not passed down from mom and dad necessarily, when you're talking about these genes turned off and turned on?
[0:06:19] Dr. Juan Ma: So yes and no, I think the majority of tumors that adults get, and I should sort of backtrack, I suppose. I think one of the biggest pieces of evidence that cancer is a genetic disease is that it's primarily a disease of old age, because we've accumulated so many mutations. So these mutations are mutations that we accumulate in our own cells, as we live through the toxic environment we live in. And so we're in the sun and we get mutations from UV, or some people smoke and they get mutations that are related to smoking, or some mutations that happen spontaneously because our cells when they divide throughout life need to copy their DNA and they make mistakes. And even though they have ways to fix those mistakes, they don't always do it perfectly. But that said, there are subsets of patients who do inherit mutations in their genes from their mom and/or dad, and that makes them at much higher risk. And so the one example that people would have thought of or come across is BRCA.
[0:07:26] Dr. Diane: Yeah, and I think that's a really important point though, when we're talking about these genes in the cell, and that there may be some genes, like you said that, for some reason, turn on. And then like you said, the gas pedal just doesn't stop. But what's amazing about the development of cancer is that one gene may have gotten damaged, but yet nothing happens by itself, right. So there's one gene turned on and then maybe a kind of scary way, years later, something else in that cell happens and then another gene gets turned on. Now two genes have the gas pedal, but yet still no cancer develops. And then eventually, like you said, then there's another gene that gets hit that's supposed to put the brakes on and no longer can. And so it is this combination of genes that are getting damaged or mutated, as we call them in our world that eventually develop into this one cell, that now, like you said, has the ability to not only grow and proliferate, but now it's sending these cascade of messages that can figure out how to spread in a way that can cause severe danger to the patient. So, when we talk about these different genes that eventually allow these cancer cells to develop, we first started to develop the treatments of traditional chemotherapies and radiation. It went after these very actively dividing cells. Now, over the last five or six decades, there's been a lot of change in terms of, can we instead of going after the cells just by traditional chemotherapies take a more targeted approach to potentially improve efficacy and potentially improve safety by going after those different genes, we call that targeted therapy. Can you talk a little bit about what that actually means? Like, what is targeted therapy, and is it really more efficient, is it really more safe? And does it help to go after that one gene that may be driving this out?
[0:09:17] Dr. Juan Ma: So I think the way you've told the story is very important, you know, a 70-80 years ago, we started to realize we -- people that were working on this started realizing there were ways that you could kill cancer cells, because they were much more sensitive to very toxic agents, whether they be radiation, or chemotherapy agents, but one of the problems is that they were very, very toxic. And so a lot of the clinical development throughout the second, third, let's -- the last third of the 20th Century was in developing the ways that we could give these agents and give these drugs to patients and have them survive because they were so toxic and you know, one of the -- probably the most important developments in the treatment of cancer weren't the drugs themselves, but the drugs that prevent the nausea that these drugs cause. And so now you could give these drugs and actually cure patients. So the example of like platinums in testicular cancer I think is really important. And I think, you know, I was thinking about this before I came here; one of the key lessons from the original studies where we learned how to treat and in many cases cure because a lot of these studies were done in paediatric patients at the NIH, was that combination treatment was important, then if you use one drug alone, the tumor cells would outsmart it. But if you use three or four or five drugs, then the tumor cells couldn't outsmart it. And then the question was, well, how can we give those drugs but have our patients survive. And so that helped develop the field of chemotherapy essentially starting with kids who with a lot of these leukemias were dying very, very quickly and now up to 90% 95% are cured with conventional chemotherapy.
So, you know, one thing I like to say is that as much as we learn and we like to develop things that are more targeted, a lot of the times the things that we think are targeted are not. But they'd also may be that things that aren't targeted are more effective. That said, as we've learned a lot more about why these cells are dividing, I think rightly, people have started to think, well, for example, if there are specific mutations that make the gas pedal go always on, are there things that we can do to say cut the gas supply or the electricity, whatever it be, to that gas pedal to stop those cells dividing. And the best example of that is Gleevec. So going back a long time now, a number of scientists discovered that certain type of leukemia called chronic myelogenous leukemia had a specific funky looking chromosome that’s called the 9;22 translocation. And eventually a lot of work showed that what had happened with those cells is that they had a new protein that didn't exist in those cells normally, and that that protein was one of these gas pedals that was always on and it was telling these cells to divide constantly. And these patients were treated with a number of different agents, but not very effectively.
So then a number of scientists develop specific drugs that block that one funky protein that doesn't exist in other cells. And sure enough, when it's given to patients with CML, patients who otherwise died of their disease are now not cured because they can't stop the drug, although those studies are ongoing, but effectively can live a normal life. And so I think that paradigm is something that a lot of people find very attractive as a way of treating, it was new, and so there's been an explosion of that sort of approach, sort of finding what is the oncogene or the gene that we think drives these tumors and seeing if inhibiting it or blocking it can stop the growth of these tumors. You know, I think it's a very good approach, and it's going to continue to lead to some improvements. But I think it's useful to think back to what I was talking about earlier about the initial approaches to cancer and using multi drug therapies, where maybe there's some truth to that, maybe there's the more toxic drugs in combination, have an added benefit that the single drug studies don't or drugs don't have. And I think one way to think about it is that tumor cells are not static. One of the things that characterizes them is that -- so I was talking before about copying DNA especially solid tumors, they're very bad at copying DNA, so they make a lot of mutations. And what that means is that it's very easy to generate new mutations that make them resistant to the drug you're given. And so if you give a single drug, oftentimes these drugs can have some effect and slow the growth of the tumor for a few months. But ultimately the tumor comes back in their resistance mutations. And so then the question is, well, can we develop another drug that treats the resistance mutation? So I think it's an approach that is going to continue to work. But in most of the cases, we're seeing small effects.
[0:14:26] Dr. Diane: Yeah, I often use in my patients is sort of analogy of the first time we treat one of our patients with stage four disease, for example, we'll get benefit as you said with those first line therapies, which are often combination treatments, because those different chemos are targeting these cancer cells in different ways. But like you said, eventually, the cancer cells that are leftover will start to grow, and so now we have the more resistant cancer cells. And I'm about to start what I call my second string players that are second line therapies that can be good but often not as good as the first, and now they're sort of trying to attack cancer cells that are little bit more resistant. So one can envision, like you said, as these cancer cells divide and grow, you often can see that they have more mutations, they tend to be more aggressive. And so the fight against each one of these treatments gets a little bit harder, if you will, to your point. So I think those are really important points in terms of this is not a one-size-fits-all, cancer has hundreds of different diseases, probably thousands if we think about it genetically. And so therefore it's definitely not a one-size-fits-all. But what often happens in our clinic, as you know, is patients will come and they'll say, what is novel and different, and one of those is sort of the idea of next generation sequencing.
And we're going to look at that in a later episode of Cancer Straight Talk, really interesting research look for next generation sequencing. I want to thank Dr. Dr. Juan Ma Schvartzman for your time and expertise. Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information or to send us any questions you may have, please visit mskcc.org/podcast. Help other people find this helpful resource by rating and reviewing this podcast at Apple podcasts or wherever you listen to your podcasts. These episodes are for you, but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical conditions. I'm Dr. Diane Reidy-Lagunas onward and upward.
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