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Flipping Switches: A Quest for Gene Mechanisms to ‘Turn Off’ Cancer

Newitt, Valerie Neff

doi: 10.1097/01.COT.0000520683.80647.88
News

Christopher Vakoc, MD, PhD, is appropriately consumed with ongoing research into gene control, yet he tells a unique story about life in the world of medical research. Instead of enumerating the immense pressures and the daily stressors, he speaks of an idyllic life bordering on a perpetual “summer camp” existence.

An Associate Professor at Cold Spring Harbor Laboratory on Long Island, N.Y., Vakoc lives with his wife, Camila dos Santos, PhD, also an Assistant Professor, who heads her own cancer lab, and their two young sons, on the Cold Spring Harbor campus.

“I'm sure you hear that a medical research career is one of tremendous demands,” said Vakoc. “Prior to having children, my wife and I worked tirelessly. We'd go to work at 8:30 a.m., come home at 10 p.m.—and that was on a ‘good’ day. But now, maintaining balance in life has become essential.” Some of that balance is found on Cold Spring Harbor's “...remarkable campus. It is a collection of cottages that are lab buildings—not urban high-rise lab buildings,” described Vakoc. “It is a charming science village, and nestled within laboratory buildings are apartment buildings and little houses. That's where we live. If you were walking down the main road here on campus, you wouldn't be able to easily tell which cottage is a residence and which is a lab. It is unusual and we absolutely love it. We have no commute, there is a daycare on campus; everything is designed to be an optimal environment to make discoveries. When we are not in the lab we can immediately flip to family time.”

Family time includes hiking through a beautiful natural landscape, kayaking the Long Island Sound, or just lulling on a front porch that overlooks the harbor. “There's a very social atmosphere on campus; it's a hub where young scientists and their families come together,” said Vakoc. “The other exceptional thing about Cold Spring Harbor is we convene international conferences here—one per week all summer long. Literally thousands of scientists from different fields visit from all over the world to discuss their research. We feel part of a global network of scientists.”

Such stimulation only adds to the intellectual vibrancy of Vakoc's own lab, which consists of postdoctorial researchers, technicians, and other assistants. “My wife and I have chosen consuming careers, with the added challenges of finding financial resources for our research, training the people in our labs, and teaching them the trade of science. It's more than a way of life, it's a passion,” Vakoc said earnestly, “and a belief that it is going to be beneficial to society. So while there is a degree of personal sacrifice, it is offset by an opportunity for creativity and insights with broad benefits—not just for medicine in the short-term, but also in the longer-term as new knowledge makes society better.”

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In the Beginning

Vakoc's passion for science can be traced back to his hometown outside of Allentown, Pa., and his seventh grade biology teacher, Pamela Nestor. “I had never thought too deeply about how life could exist. I just knew I woke up in the morning, ate my breakfast, and had an awareness of being alive. I never really thought, ‘What is life? Is there machinery that makes this possible?’ Then one day, Mrs. Nestor casually mentioned that all of life has an operating system—the same operating system. She said there is this thing called DNA and it defines a lot of our biological makeup. She said it is very tiny, and it can be thought of as a series of letters that creates a code 3 billion letters long in a human being, and different lengths in other organisms. And she said all types of life—whether a plant, insect, bacteria, virus, or man—all are using the DNA molecule as its operating system. She said it's not some type of cosmic coincidence that this occurs, but rather the reason why all life forms operate this way is because they all have a common ancestor that has this operating system, from which all life forms are descended. I was absolutely floored by this. I get chills just thinking of it now.”

Learning that a DNA operating system unites all life “... was a profound outlier—the most fascinating and profound thing I'd ever learned in my life,” declared Vakoc, who went on to earn MD and PhD degrees in a joint degree program at the University of Pennsylvania, Philadelphia. “At the time, I had the drive and the curiosity to pursue both, but not much realistic understanding of a clinical versus a research profession. Out of that indecisiveness, I went for the joint degrees. But my ambition and confidence were quickly put in their places; it was hard to be really good at two things. I eventually felt I could be a successful researcher, but only a mediocre doctor. I got to know myself.”

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In the Lab

Vakoc speaks with almost boyish enthusiasm about his current area of research. “The thing that really set the hook in my mouth was thinking about how genes work; how DNA is turned on and turned off—a field often referred to as epigenetics,” he explained. “This is the science of gene control. The DNA operating system is found throughout the body, but each part of the body—each cell—uses that DNA dramatically differently. Cells can read the letters of DNA and say, ‘OK, I'm only going to read this sequence of letters.’ The question is: how does a cell do this?”

Vakoc said everything that cells do basically comes down to mechanics. “If you were to look inside of a cell, you would see tens of thousands of little machines made of protein wiggling around and carrying out very mechanical processes,” he detailed. “So, in my lab, we are studying the ‘machines’ that are involved in the flipping of DNA from an ‘off’ to an ‘on’ state, or vice-versa.”

Having studied in “respectable detail” how the machinery can flip DNA from off to on, Vakoc said, “We understand it in pretty phenomenal detail. It is arguably one of the most important pursuits in all of biology. We already know how to flip these switches in DNA, so my lab is interested in knowing if it is possible to flip these switches in disease in an organism, and particularly in a human. Can we flip genetic switches with medicines? How might we take a disease like cancer, with cells growing uncontrollably, and flip the right switch and strip cancer cells of their problematic features. We have been designing our research around this question.”

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Finding Answers

While some of Vakoc's research looks at the dark side of cancer—understanding how cells go wrong—it also looks at the light side—how to make cells go right. “Perhaps even more on the good side, we are trying to discover which switches we can flip to undo the damage that a cancer cell has inflicted. It has been a productive and rewarding avenue,” said Vakoc. “We ask, ‘Which switch can we flip to do harm to cancer cells but not do harm to the body?’”

To date, Vakoc and team have found many such switches. “Some we discovered were unknown before, so fundamentally we are learning new things about how cells work,” he noted.

Some of these projects have fortuitously led to therapeutic applications. “It is basic research—and to be clear, that does not mean ‘simple’ or less challenging. It means it is curiosity-driven and the goal is to produce knowledge as the primary endpoint of what we do. Nevertheless, we do a lot of our research in cancer cells, so naturally we are always on the lookout for opportunities where we might act upon something we've just learned.”

The most mature example of such a finding is the lab's identification of a molecular switch that could be flipped to cause harm in a type of leukemia. The switch is called Brd4,” said Vakoc. “During one of our hunts for cancer-harming switches, we just tripped over Brd4 and found it. We thought, ‘Wow, that's cool, no one else studied that before in leukemia. Let's dig in.’” Eventually, the team was alerted to another lab that had developed small-molecule drugs that hit this particular switch, for reasons unrelated to leukemia. A phone call between labs ensued, and the Brd4 drug sample was sent to Vakoc.

“We studied leukemia in mice that had been given the aggressive disease modeled after the human condition,” recalled Vakoc. “We treated them with Brd4 drugs, and to our satisfaction this inhibited the leukemia in the mice and did not harm normal tissues. The mice that were treated lived longer.”

After findings were published, other labs replicated the work (Nature 2011;478(7370):524-528). “Within 2 years of our 2011 paper, the first human clinical trials opened up with several different companies testing Brd4 inhibitors for leukemia and other cancers as well. A phase I trial was initiated to see if Brd4 inhibitors were safe and if there is any evidence of activity in patients who had failed prior therapies. It is very satisfying.”

The first paper on the phase I trial of Brd4 inhibitors was published in 2016 (Lancet Haematology 2016;3(4):e186-195). A subset of patients in this trial, all of whom had failed prior therapies, had responses, “... some even complete remission of their disease—after being treated with Brd4 inhibitors,” said Vakoc.

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The Final Analysis

Yet it remains research for the sake of new knowledge that really hums for Vakoc. “What is always on my mind is how these genes turn off and on. While improving human health is an incredibly important objective of our research, we also see an equally important role of our research in producing fundamental knowledge of how cells and genes work,” he said. “All biomedical discoveries have to start somewhere, they don't materialize out of nowhere. We cannot always expect a quick return on our investment in basic research, but history teaches how the long-term investment of our society on producing knowledge and technology can have profound medical and economic benefits to everyone.”

Asked to describe his overarching efforts as they pertain to cancer, Vakoc responded, “Now, more than at any other point in the history of cancer therapy, we are aware that one cause of cancer is epigenetic processes, that is, DNA switches being turned on and off. It is so clear and it is striking. For that reason, we are pursuing the hypothesis that flipping these switches back to where they were in the pre-cancer state is how we are going to go about treating cancer. Yet there are other compelling strategies for treating cancer, like turning the immune system on to attack cancer cells. Maybe it will be the switches in the immune system that will be flipped to kill the cancer cells. The concept is a broad one; it is not one flavor.

“If we can develop a multitude of medicines that can flip any single gene in our genome from off to on, or on to off, we could overcome many illnesses. Every disease would have an opportunity for treatment. While this might seem overly optimistic when considering the enormity of human disease today, as scientists we work tirelessly in the lab with a belief that everything is possible,” declared Vakoc. “It is just a matter of figuring it out. It is not if, it is when.”

Valerie Neff Newitt is a contributing writer.

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