Pediatric cancer—two words that carry immense weight. For many, it’s a distant fear; for some, it’s a daily reality. And for my family, it became a devastating truth. After losing our teenage daughter to a rare form of cancer, we were left with a haunting question: Why are these cancers so difficult to treat?
In this episode, I speak about the topic with someone who has made it his mission to uncover pediatric cancer’s secrets. Chris Vakoc is the Alan and Edith Seligson Professor of Cancer Research at Cold Spring Harbor Laboratory. As a molecular biologist, it’s his job to ask difficult questions. Each day, his lab pushes the limits of current knowledge, searching for ways to reprogram cancer cells and interfere with the processes that help these diseases thrive.
Join us as we explore the wondrous world of cells and genes, where the battle against pediatric cancer is fought not just with microscopes and molecules, but with relentless hope and ingenuity. It’s a story of curiosity, discovery, and the pursuit of answers that could change lives.
Transcript
Phil Renna: Hello, fellow science fans. Thank you for joining us At the Lab, where we talk about inspiring curiosity, discoveries, innovation, and the many ways that science makes life better. From Cold Spring Harbor Laboratory, my name is Phil Renna, and today we’re discussing pediatric cancer research. Before we get started, we invite you to subscribe to our regular podcasts and share out your favorite episodes. Science is always better when explored together.
PR: Now to our topic and today’s guest, Dr. Chris Vakoc, a professor here at Cold Spring Harbor Laboratory. Let’s dive in. Chris, to give some background to our audience, can you share your journey into cancer research and what specifically led you to pediatric cancers?
Chris Vakoc: Yeah, thanks, Phil. It’s a pleasure to be here and talk to you today. My training and research began as a Ph.D. student. I studied genes, how they’re regulated, and how they participate in blood formation. And that occurred at the Children’s Hospital of Philadelphia. I then came to Cold Spring Harbor to start my own independent research laboratory. My fascination with genes and how they’re controlled continued, but I pivoted to the investigation of cancer, which is a disease profoundly influenced by genes and gene regulation.
CV: I began studying malignant hematopoiesis, a specific disease called acute myeloid leukemia. And over the last 16 years, I’ve been running a laboratory that seeks to understand how genes and the way in which they’re controlled drive the pathogenesis of a variety of human cancers. We began in acute myeloid leukemia, subtypes of leukemia that occur in children.
CV: We’ll get more into this, I’m sure. But I’ve always had a passion for cancers that afflict the young. Over the years, this has evolved into studies of sarcomas, carcinomas. We work on a lot of different cancers, but the common thread is our genes and control mechanisms of genes.
PR: I often hear that most adult cancers have accumulated many more genetic mutations, whereas pediatric cancers tend to have fewer. Is this why they are more difficult to treat?
CV: Yeah, that’s absolutely truth. When people have counted genetic mutations in childhood cancers versus adult, yes, there’s a striking difference in how many faulty genes a cell needs to become a childhood cancer. And yes, and there’s a practical consequence of this, because the newest mode of new therapy development involves targeting mutant gene products. There just aren’t that many to choose from for childhood cancers. In a childhood sarcoma, for example, you might have one major driver genetic change. It’s one opportunity for pharmacology development. In an adult tumor, you might have multiple genetic changes, and it just gives you a few more opportunities, not excessive numbers for adult tumors. But it’s one restriction.
CV: But why are childhood cancers caused by fewer mutations? I think this developmental window of time, it’s almost substitutes for mutations. A patient needs less mutations because that developmental window is already programing a cell to grow and develop. And it just puts the cell close to the edge of forming a tumor so that fewer genetic mutations are needed to kind of push the cell over the edge for uncontrolled growth. And so studying that developmental window of time and the epigenetics of this is a major priority of the field, a major focus of my own research. And it’s really where many of us believe future cures for pediatric cancer can be found.
PR: Chris, can you describe the tools you use to understand cancer and its complexities while still searching for the best drug targets?
CV: Yeah, inspired by the many scientists at Cold Spring Harbor who came before me, I’ve been fascinated by the technology for manipulating genes. We’ve been investing heavily to develop and implement tools that allow us to manipulate genes in a high-throughput way in cancer models. And so a common experiment in my laboratory is we take a model of cancer, like a pediatric sarcoma, and we apply molecular technology to inactivate every gene in the genome.
CV: And essentially what we’re doing is subtracting macromolecules, targets from tumor cells. And without the tedious process of drug development, we can kind of figure out which molecules inside of a cell are worth targeting, which could allow for melting away of tumor tissue and safely without harming normal organs. We can find some of these targets early, without the multibillion-dollar drug development investment. We can do this much cheaper than that and in a high throughput way in the research laboratory. And effectively, it’s target discovery research.
PR: Chris, this is exciting work that your lab does. I know you also work in sarcomas and use CRISPR to find drug targets. For a lay audience, can you give us an overview of how you take tumor cells and hopefully identify drug targets?
CV: Yeah, so I have a team of usually at any one moment, somewhere between 16 and 20 scientists, some of whom are Ph.D. students, medical students, physicians, senior staff scientists, people from right around the corner here in Long Island, some from the other side of the Earth. What they all have in common is this passion for drug target discovery and for studying the fundamentals of gene regulation.
CV: When these individuals join my lab, usually the first thing they learn how to do is how to take cancer cells that came from a patient, and learn how to cultivate them in the laboratory. That involves cells adapting to the growth in plastic dishes. Obviously, human tumors don’t grow on plastic, but we need them to grow in plastic so that we can culture them safely. These cells don’t want us to manipulate them. They just want to grow and perpetuate this disease. And so we spend several months just figuring out how to take care of these tumor cells and how to trick them out into doing what we want them to do.
CV: These individuals in my lab might spend a year doing what we call screens, and that involves these high-throughput manipulations where we manipulate thousands and thousands of molecules inside of these tumor cells, and we’re kind of sniffing around for powerful anti-cancer therapeutic effects. Hunting is a better word. And once we’ve found a gene we’re extremely excited about, that kind of kicks in motion phase two of the research project, where we found a cool target, we think it could be a future cure for this cancer, but the goal is to figure out why.
CV: We need to understand why a gene and its protein product is driving a cancer. Without understanding how it works on a mechanical level, our research does not have value. And we’re not trying to just find a quick cure and rush to the clinic. It’s this deep molecular understanding that is part of the brand of Cold Spring Harbor research that’s recognized around the world. And I feel a lot of inspiration to kind of continue that rock solid tradition of science at this kind of hallowed grounds for research.
PR: So, yes, obviously, the foundational work that’s being done at Cold Spring Harbor Laboratory into the understanding of cancer is ultimately so important for discovery. I have a question relating to the points you just made: The relationship of collaboration with other institutions, other scientists here at the laboratory, and other advocacy groups and philanthropy for your cause.
CV: There is a tension in our research, which is that we receive funding from philanthropies from families that have lost children to these devastating diseases. And you know this better than anyone, Phil. There is a pressure to fix this disease as quickly as possible. Speed. We are kind of encouraged to be fast and get things to the clinic. Fix this disease so no future child has to suffer. And we feel that pressure in everything we do.
PR: But we know that’s not the best way science works.
CV: Well, again, there’s a tension, and I want to like explain this because we work fervently seven days a week, 12 hours a day usually, to do this research. It is a passionate cause that we are working towards, to make discoveries and to move them to the clinic for application as quickly as possible. However, the tension is that we also need to make sure we’re right, and we need to make sure we understand what we’re doing.
CV: Clinical trials fail. Getting to the clinic is not meaningful. Succeeding in the clinic is what matters. And there are many reasons why a lot of new drugs that go into the clinic and get tested in kids with cancer fail. But one way that we can make this better is to deepen our understanding of the best targets out there. And so we have an obligation to explain to the people that are supporting us that while we do work aggressively, we also need to work carefully. And these things are not always compatible. And so sometimes you have to pump the brakes. Sometimes you pump the gas. And we’re always making those strategic calculations along the way in our research.
CV: This is not like treating a bacterial infection, a foreign species growing in your body. These are your own cells. These cells have more in common with your own body than they do with another species. So, the differences that we have to manipulate/exploit to make therapies are so few. And so we are up against an incredibly hard problem.
CV: And you know, I would argue that pediatric cancers are one of the most challenging diseases that humanity is faced with. And we have to kind of recognize the challenge and that there aren’t a lot of quick in-out opportunities to rush things forward. And so we balance the long-term game with the short-term game.
PR: Chris, I have to say, I know for myself, even explaining to my funders that just because something didn’t work, that wasn’t a [negative] outcome. You know, if you figured out that mechanism, but you couldn’t hit that target, well, now you move on to the next one. And that’s the process of science that, you know, you probably have racked up a ton of failures as you go down this path to find the one or two things that might work. And that’s the story that people don’t understand in general. And I appreciate the fact that you’re bringing that out because people need to understand science is a process.
CV: Yeah, and this is a deeper topic now, a broader topic, but, you know, an investment in science is an investment in the individuals you’re supporting and believing in their genuine curiosity. The one thing that I’m struck by: The biggest discoveries in the history of biology, most of them happened by accident, not because you promised someone you would find something in two years and then you found it. It’s usually because you were careful, you were thoughtful, and you just by digging deeper into what you’re studying, you trip over something profound. And usually it’s the prepared mind that realizes what they’ve tripped over.
CV: Invest in people. Find scientists that have those characteristics and invest in them, and diseases will drop. The folks that are telling you that they will guarantee a cure in X number of years, you know, these are the things to be suspicious of.
CV: And I think investing in this is what real science is. And that has never changed. And as much as we direct our research towards finding cures, we also have to tolerate that discoveries happen unexpectedly. And we have to recognize that that is how discoveries get made. And that’s an uncertainty that a lot of people don’t feel comfortable with when they’re investing their money into someone. Is someone really being honest in that promise that science is unpredictable, or not? And so I think that’s where we as scientists have a challenge to communicate the way we approach things in a goal-directed manner, but in a way where we anticipate unpredictability.
PR: Chris, this next question we asked all of our guests. What keeps you up at night, and what’s the one question that you really want answered?
CV: Finding a cure for pediatric sarcomas is a major objective of my entire career and my life. But what keeps me up at night is whether there’s an unexpected discovery in our research that happened that day that I may have missed. Was there something?Was that big discovery lying in plain sight? But it wasn’t what we expected, so we maybe overlooked it.
CV: I lose a lot of sleep about whether these mysterious observations we just missed them because again, we thought our goal was this but it actually should have been that. And finding these accidental, serendipitous discoveries, I think is the hardest thing to prepare oneself for. And I think at the end of the day when my thoughts are racing about what I thought about during the day, looking at science, looking at data, it’s that. What have I missed?
PR: Chris, if you could tell someone one thing about your work, what would it be?
CV: I would say all human diseases are modified by our genes. And if we can understand how nature controls genes naturally in life, I think there’s every reason to think we can have medicines that control how our genes behave. And this would be the ultimate tool to mitigate human disease. And so I think understanding how genes work, which is the bedrock, the soil of Cold Spring Harbor historically. People have been coming to this campus for over 100 years to marvel and understand the gene. And I’d like to think of myself as one person in that long-term tradition. And through its modern lens, we’re trying to cure disease with this knowledge, but it is fundamental knowledge of the gene that continues to drive research on this campus.
PR: Science is a shared collaborative story. Discovery and innovation come from the curiosity inherent in each of us. Thank you for supporting science by listening and learning right alongside us. If interested in more news about Cold Spring Harbor Laboratory research, subscribe to this podcast, sign up for our newsletter, and follow us on social media so you can share with us how science impacts you. To philanthropically support research at Cold Spring Harbor Lab, visit give.cshl.edu. Because science makes life better.