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Christopher Vakoc

Camila dos Santos speaks at the Pershing Square Research Alliance’s Fifth Annual Prize Dinner at the Park Avenue Armory on May 23 with Bill Ackman, co-founder of the Pershing Square Sohn Foundation and CEO of Pershing Square Capital Management, and Olivia Tournay Flatto, the President of the Pershing Square Foundation.

By Daniel Dunaief

They aren’t quite wonder twins, but some day the dedicated work of husband and wife scientists Christopher Vakoc and Camila dos Santos may help people batting against a range of cancers, from leukemia to breast cancer.

An assistant professor at Cold Spring Harbor Laboratory, dos Santos recently won the prestigious and highly coveted Pershing Square Sohn prize. Dos Santos, who studies breast cancer, will receive $200,000 in funds per year for the next three years. She won the same prize her husband, an associate professor at Cold Spring Harbor Laboratory, collected two years earlier for his work using the gene-editing technique CRISPR to study the molecular pathways involved in leukemia.

Dos Santos and Vakoc are the first family of prize winners in the Pershing Square Foundation’s five years of supporting research in the New York area.“The board was very much taken by how original her approach is and how thoughtful she is about it,” said Olivia Tournay Flatto, president of the foundation. “There was a lot of early stage data that would say that the observations she’s making are interesting to pursue, but that the National Institutes of Health would not fund. We felt this was something we wanted to be a part of.”

Dos Santos is studying so-called epigenetic changes that protect women from breast cancer if they become pregnant before they are 25. Women who have pregnancies before that cut-off age have a 30 to 40 percent decrease in breast cancer, even decades after their pregnancy.

Dos Santos has been digging into this process, looking at why some women who are pregnant before this age still develop breast cancer later in life.

The Cold Spring Harbor scientist is exploring how infections block the protective effects of pregnancy. She hasn’t defined the panel of infections that could influence cancer risk before or after pregnancy. The hypothesis in her work is that “the whole process that is fighting inflammation could change the breast cells,” which could “take away the advantage that pregnancy brings.”

If she proves her theory — that changes to inflammation could take away benefits of an early pregnancy — she could define changes to proteins and genes as biomarkers to predict the risk of breast cancer, even in the event of an early pregnancy. One of the challenges in the three-step application process for this prize was to explain to a group of experts how what she’s doing was different from what others are pursuing. Her approach is to look at cells before and during the process of turning into cancer cells. That strategy led to the current hypothesis, which was the basis for her application for this prize.

To study breast cancer, dos Santos recently developed a mouse model in her lab, to see how pregnancy changes pre-malignant lesions. When the mice they are studying have a gene that would turn into cancer, some of them don’t develop cancer if they’ve already been pregnant. Those mice that haven’t been pregnant develop cancer. She uses this mouse model to ask questions about how pregnancy changes a cell such that oncogenes cannot operate to change a cell into a cancer.

“We are not only investigating how prevention works, but we are also learning what signals break that prevention,” dos Santos said.

Dos Santos has used the mouse model experiments to test an unusual element to human breast cancer resistance. Women who reach their second trimester before 25, but don’t give birth to a child, have the same resistance, decades later, to breast cancer. Mice whose pregnancies last through the equivalent of the second trimester also experience similar epigenetic benefits.

She has tested mice who have a pseudo-pregnancy —who have higher pregnancy hormone levels without being pregnant — to see if a similar pregnancy environment would convey the same resistance. “Even in those cases, with no fetus, no embryo, no birth and no nursing, we see that the epigenetics changes,” dos Santos said. The scientist plans to use the funds from this award to perform high-tech experiments, such as single-cell, multiple mouse models and human tissue analysis that she wouldn’t have been able to tackle without the funding.

Dos Santos is grateful for the funding, which she said she wouldn’t have been able to secure through other means based on “the stage we are right now,” she said. The work is “risky” and “provocative,” but it’s also “outside of the box ideas and experiments and approaches.”

When she puts all the variants together, the risky outcome could be beneficial, leading to a better understanding of how to copy or, perhaps, understand nature to try to cure or prevent cancer.

Dos Santos said she learned about the award when she was on a train on the way to Jamaica, where she was catching a flight to Washington, D.C. She said she turned into a “texting machine,” sharing the good news with everyone, including her husband Vakoc, who called her as soon as he saw the news. “He was super happy,” she recalled.

She said Vakoc was particularly helpful in discussing the work and in watching their sons Lucas and Marcus who are 8 and 5, respectively. She also received some unexpected help from him before an extensive seven- to eight-minute finalist screening process.

She asked him about the interview, and he remembered that there were five people in the audience and that he didn’t get that many questions. When she appeared for her interview, she saw about 25 people in the audience and received numerous questions. In a way, she said, his memory of his experience may have helped her, because she didn’t have time to worry about the size of the audience or the number of questions.

Dos Santos said their sons are proud of their parents for winning awards for their work on cancer.

When her sons are upset with dos Santos, they sometimes warn, reflecting their parents’ threat to take away TV, that they’re going to “take your epigenetics away.”

Dos Santos said the couple maintains a healthy work-life balance. She is grateful for her husband’s support, as well as for the environment and expertise at Cold Spring Harbor Laboratory.

“Here at the lab, we not only have the technology to move this forward, but we also have a pretty outstanding body of scientists that are very collaborative,” she said.

Yali Xu and Christopher Vakoc at the 2013 Don Monti Memorial Research Foundation’s Anniversary Ball. Photo from Yali Xu

By Daniel Dunaief

It’s like a top scorer for another team that the greatest minds can’t seem to stop. Whatever they throw at it, it seems to slip by, collecting the kinds of points that can eventually lead to a life-threatening loss. The scorer is a transcription factor called MYB, and the points it collects can, and often do, lead to breast and colon cancer and leukemia.

Researchers have known for over 30 years that stopping MYB could help with cancer treatment. Unlike other possible targets, however, MYB didn’t seem to have the kind of structural weakness that pharmaceutical companies seek, where developing a small molecule could prevent the cancer signals MYB delivered. Some researchers have decided that drugs won’t stop this high-profile cancer target.

Cold Spring Harbor Laboratory Associate Professor Christopher Vakoc and his graduate research assistant Yali Xu, however, have figured out a way around this seemingly intractable problem. The CSHL scientists recently published their results in the journal Cancer Cell.

MYB binds at a small nub to a large and important coactivation protein called TFIID (which is pronounced TF-two-D). This protein is involved in numerous life functions and, without it, organisms couldn’t survive. Vakoc and Xu found that they could use a small peptide decoy to trick MYB into believing it had attached to this protein when, it reality, it hit the equivalent of a molecular dead end.

In a mouse model of acute myeloid leukemia, this peptide caused leukemias to shrink in size by about 80 percent. “What we’ve discovered is head and shoulders above anything we’ve come across before,” Vakoc said.

As with many scientific discoveries, researchers have to clear numerous hurdles between this conceptual discovery and any potential new cancer therapy. “This is not a medicine a person can take,” Vakoc said.

Indeed, scientists and pharmaceutical companies would need to study what leukemia cells escaped this type of treatment to understand how a cancer might rebound or become resistant after an initial treatment. “Our goal is to develop something with longer lasting effects” that doesn’t become ineffective after three to six months, Vakov said. He described understanding the way a disease reacts to a treatment as an “arms race.” Nature inevitably “finds a way to outsmart our decoy. We’d like to know how [it] does it. We’re always trying to study both sides and trying to anticipate” the next steps.

Down the road, Vakoc could foresee researchers and, ultimately, physicians using this kind of approach in combination with other drugs or therapies, the way doctors now provide patients who have the HIV infection with a cocktail of drugs. Conceptually, however, Vakoc is thrilled that this work “highlights what’s possible.”

One of the most encouraging elements of this approach, Vakoc said, is that it combats MYB without harming organ systems. When the researchers gave the treatment to rodents, the mice were “running around, eating and gaining weight.” Their body tissues appeared normal, and they didn’t demonstrate the same sensitivity that is a common byproduct of chemotherapy treatment, such as losing any hair or having problems in their gut.

An important step in this study, Vakoc said, was to understand the basics of how MYB and TFIID found each other. That, Xu said, was one of the first steps in her graduate work, which took about five years to complete.

In Vakoc’s lab, which includes 13 other researchers, he described how scientists make thousands of perturbations to cancer and normal cells, while they are hunting for cancer-specific targets. By using this screening technique, Vakoc and his team can stress test how cancer cells and normal cells react when they are deprived of certain proteins or genes.

“This began as a screen,” he said. “We took leukemia and normal blood cells and did a precise comparison of the perturbation.” They searched for what had the most specific toxicity and, to their surprise, found that interfering with the binding between MYB and TFIID had the strongest effect. “Once we understood what this nub was doing, we applied all kinds of biochemical assay experiments,” Vakov added.

Ultimately, the peptide they found was a fragment of a larger protein that’s active in the cell. Vakoc credits Xu for her consistent and hard work. “When we started on this hunt, we had no idea where this was headed,” he said. Xu was “relentless” in trying to find the answers. “She pieced it all together. It took a great amount of imagination and intellect to solve this puzzle.”

Vakoc suggested that Xu, who plans to defend her thesis this spring and graduate this summer, has set a great example for the other members of his lab. “I now have 13 other people inspired to outdo her work,” he said. “We know we have a new standard.”

Xu is grateful for the support she has received from Vakoc and appreciates the journey from her arrival as a graduate student from China to the verge of her graduation. “It’s very satisfying when you look back and think how things evolved from the beginning to the end” of her graduate work, said Xu, who lives near Huntington Village and enjoys the chance to visit local restaurants and sample coffee and ice cream when she isn’t conducting research toward her doctorate.

The scientific effort, which was published recently, has attracted the attention of others, particularly those who are studying MYB. Vakoc recently received an email from members of a foundation that is funding research on a solid tumor in which scientists believe MYB plays a role. He is writing grants to get more financial support to pursue this concept. Vakoc is encouraged by the opportunity to make progress with a protein that has been “staring [scientists] in the face for three decades.”

Camila dos Santos photo from the scientist

By Daniel Dunaief

Mothers of more than one child have blogged about it for years. When they have their second child, the breastfeeding process is often quicker, with milk available sooner than for the first child. Camila dos Santos, who became an assistant professor at Cold Spring Harbor Laboratory in February, has found a reason.

Cells in the mammary gland go through something called epigenetic changes. That means something affects the genetic machinery, causing them to react differently under the same circumstances. In mouse models, dos Santos discovered changes in cell proliferation and milk production genes to the hormones estrogen and progesterone.

When she was a postdoctoral student in Greg Hannon’s laboratory at CSHL, dos Santos said they “decided to profile the epigenome before and after pregnancy.” At first, she was looking for changes associated with the effects of pregnancy on breast cancer development. The recent work, however, described the presence of epigenetic memory of past pregnancies, which influences milk production in the next pregnancy.

The message from these studies was that those areas where she saw changes “are associated with the genes responsible for lactation and the proliferation of the mammary gland during pregnancy,” said dos Santos.

The implications of this research extend from the potential to enhance breastfeeding in women who struggle during lactation to breast cancer.

Indeed, other studies have shown that women who become pregnant before 25 have a lower risk for all types of breast cancer.

“We believe that such strong protective effect must have an epigenetic basis,” dos Santos said. She would like to “understand how this stable, pregnancy-induced epigenome prevents cancer development,” she continued.

Hannon believes the kind of research dos Santos is conducting holds promise.

“The world of breast cancer prevention is badly in need of very solid underlying molecular biology and I think there’s a fair chance that what [dos Santos] is doing will eventually get us there,” said Hannon, who recently left Cold Spring Harbor Laboratory and is now the Royal Society Wolfson Research Professor at the Cancer Research UK Cambridge Institute at the University of Cambridge.

Dos Santos said her research is exploring ways to turn the changes that occur during pregnancies before the age of 25 into a “preventive strategy to treat women that are high risk and even those that are not.”

To be sure, Hannon and dos Santos cautioned, it’s difficult to know how quickly or even whether this kind of research will lead to any treatment or prevention options.

“The main goal of my lab is to try to understand the effects of pregnancy on normal cells, to devise a strategy to prevent breast cancer from arising,” dos Santos said. She recently published her work in the journal Cell Reports.

Dos Santos and Andrew Smith, a computational biologist from the University of Southern California, along with his postdoctoral fellow Egor Dolzhenko discovered that mice that had been through a single pregnancy had methylation marks that were different from mice of the same age that hadn’t been pregnant. The group connected the changes in the genome to a transcription factor called Stat5a. A transcription factor is a protein that acts like a genetic traffic light, turning on or off genes.

When she joined Hannon’s lab in 2008, dos Santos wanted to study gene regulation throughout cell development. It took her three years to purify stem cells.

Hannon credits dos Santos for developing new techniques.

“She had to build the tools she needed to ask” these questions, Hannon said.

Dos Santos lives in campus housing with her husband, Christopher Vakoc, who is an assistant professor at CSHL. The couple take their young sons hiking and can’t wait for the spring and summer because they hike, swim and kayak. Vakoc and dos Santos met when they were in adjoining labs in Philadelphia.

“We used to have joint lab meetings and one day he asked me on a date,” she recalled.

This summer, dos Santos’ lab will include a premed undergraduate student from Hofstra and high school students from Cold Spring Harbor High School and  Southampton High School. She recently hired a postdoctoral fellow.

“I envision my lab growing according to my needs,” she said. “Right now, I want to continue to work at the bench while training students and postdocs.”

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