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Chris Vakoc

Christopher Vakoc. Photo from CSHL

By Daniel Dunaief

Diseases like cancer take the normal raw materials of a cell and make them a part of a pernicious process that often threatens a person’s health.

Ideally, when researchers find the raw materials cancers need to survive, they discover specific proteins that are necessary for cancer, but aren’t critical for healthy cells.

That appears to have happened recently in the lab of Cold Spring Harbor Laboratory Professor Chris Vakoc in the study of the blood disease Acute Myeloid Leukemia, or AML.

Vakoc’s former graduate student Sofya Polyanskaya, who now works in a pharmaceutical company in Germany, discovered the importance of an understudied protein called SCP4, which removes phosphate groups from other proteins, in some forms of AML. This protein acts as an enzyme, which makes it a particularly appealing target.

In his lab, Vakoc said he and his researchers take “genes and the proteins they encode and [try to] publish the first paper linking them to cancer,” Vakoc said.

Polyanskaya and Vakoc recently published their findings in the journal Cell Reports.

These scientists disabled proteins in a host of diverse cancer types, looking for dependencies that were unique to each cancer. After determining that SCP4 was only needed in leukemia and not other cancers, they inactivated the protein in normal, healthy blood cells and found that it wasn’t needed.

“Leukemia cells are super sensitive to the loss of this enzyme,” Vakoc said.

Vakoc praised the work of Polyanskaya, who he said conducted the “inspiring work” that led to this conclusion. “It’s not easy for a brand new scientist entering the field to write the first cancer paper on a target.”

Polyanskaya surveyed hundreds of these enzymes to find a potential new protein that cancer, specifically, might need. The CRISPR technology, which didn’t exist nine years ago, provides a way of altering a large number of potential enzymes to find the ones that are critical for cancer’s survival.

Ideally, this kind of analysis enables researchers like Polyanskaya and Vakoc to focus in on the ones that are critical to cancer, but that don’t perform any important function in normal cells.

One of the other benefits of this work is that it validates the importance of targets that have become the focus of other research projects.

“Part of what we’re doing is making sure that our processes more broadly in the field are robust,” Vakoc said. “We are more confident in other targets we didn’t discover” but that play a role in the progression of leukemia.

To be sure, the discovery of the SCP4 target is the first step in a series of questions that may require considerable time and resources to ensure a reliable and safe clinical benefit.

As with many cancers, leukemia may have the equivalent of a back up plan, in case this seemingly important enzyme is unavailable. Indeed, the battle against cancer and other diseases involves moves and counter moves by pharmaceutical and biotechnology companies and the diseases they battle.

Additionally, researchers like Vakoc need to discover the reason cells produce this enzyme in the first place. Mice lacking SCP4 are born, but develop metabolic stress after birth.

“The important experiment in the future will be to determine what the consequences of targeting SCP4 are in normal tissue much later after birth,” Vakoc explained in an email.

Like other cancers, leukemia is a heterogeneous disease, which is another way of saying that not everyone with the disease has the same symptoms and prognosis and not everyone would respond to the same treatment in the same way.

Vakoc would like to figure out for “which subset of patients with leukemia is this protein the most important. Down the road, that could help determine who might benefit from an SCP4 inhibitor.

“We want to personalize therapy as much as possible,” he said.

In his follow up research, Vakoc hopes to learn more about the three-dimensional structure of the protein complex.

Vakoc’s interest in leukemia stems from his interest in studying blood. When he conducted his PhD training at the University of Pennsylvania, he studied normal blood development.

He was particularly interested in pediatric cancer. While AML is on of the cancers that children can develop, it is far more common in elderly people.

The lab has a strong focus on leukemia.

Vakoc, whose lab is next door to CSHL Cancer Center Director David Tuveson, has also starting searching for potential therapeutic targets in pancreatic cancer.

He is excited about the potential to bring attention to a possible candidate that may provide a therapeutic benefit for patients at some point.

“It feels good to put a new target on the map,” he said.

The CSHL scientist recognizes that cancer can and often does develop resistance to a treatment that tackles any one enzyme or protein. Still, he said treating cancer with any new and effective therapy could extend life by several months, which are often “very valuable to patients.”

Vakoc suggested that any potential new treatment for leukemia would likely involve several drugs working together to stay ahead of cancer.

“The real hope and optimism is that, if you had a copule of targets like this that are not needed in healthy cells, you could add 10 or 20 years of high quality life. You could keep the disease in a chronic, latent state.”

Tim Sommerville. Photo by Brian Stallard, 2018/ CSHL

By Daniel Dunaief

Many research efforts search for clues about the signals or processes that turn healthy cells into something far worse. Scientists look at everything from different genes that are active to signs of inflammation to the presence of proteins that aren’t typically found in a system or organ.

Tim Somerville, a postdoctoral researcher in Chris Vakoc’s laboratory at Cold Spring Harbor Laboratory, recently took a close look at a specific protein whose presence in a high concentration in pancreatic cancer typically worsens the expectations for a disease with an already grim prognosis.

This protein, called P63, has a normal, healthy function in skin cells for embryos and in maintaining normal skin for adults, but it doesn’t perform any important tasks in the pancreas.

Tim Somerville at Cold Spring Harbor Laboratory. Photo by Brian Stallard, 2018/ CSHL

Somerville wanted to know whether the protein appeared as a side effect of the developing cancer, like the appearance of skinny jeans someone wears after a diet starts working, or whether it might be a contributing cause of the cancer’s growth and development.

“What was unclear was whether [the higher amount of P63] was a correlation, which emerges as the disease progresses, or something more causal,” he said, adding that he wanted to find out whether “P63 was driving the more aggressive features” of pancreatic cancer.

Somerville increased and decreased the concentration of P63 in tissue cells and organoids, which are copies of human tumors, hoping to see whether the change had any effect on the cancer cells.

The postdoctoral researcher knocked out the amount of P63 through the use of CRISPR, a gene-editing technique. He also overexpressed P63, which is also a transcription factor.

“From those complementary experiments, we were able to show that P63 is driving a lot of the aggressive features of cancer cells,” Somerville concluded. “Rather than being a correlation that’s observed, it is functionally driving the cancer itself.”

Somerville recently published his research in the journal Cell Reports.

As a transcription factor, P63 recognizes specific DNA sequences and binds to them. With P63, Somerville observed that it can bind to DNA and switch on many genes that are active in the worse form of pancreatic cancer. He and his collaborators describe P63 as a master regulator of the gene program.

Pancreatic cancer is often discovered after the irreversible conversion of normal, functional cells into a cancerous tumor that can spread to other organs. It also resists chemotherapy. Research teams in the labs of Vakoc and Dave Tuveson, the director of the Cancer Center at CSHL, and other principal investigators at CSHL and elsewhere are seeking to understand it better so they can develop more effective treatments.

Tim Somerville. Photo by Yali Xu

Vakoc was impressed with the work his postdoctoral researcher performed in his lab. Somerville is “one of the most scholarly young scientists I have ever met,” Vakoc explained in an email. “He is simply brilliant and thinks deeply about his project and is also driven to find cures for this deadly disease.”

At this point, Somerville is pursuing why P63 is activated in the pancreas. If he can figure out what triggers it in the first place, he might be able to interfere with that process in a targeted way. He also might be able to think about ways to slow it down or stop the disease.

The form of P63 that is active in the pancreas is not a mutated version of the protein that functions in the skin. If scientists tried to reduce P63, they would need to develop ways to suppress the cancer promoting functions of P63 without suppressing its normal function in the skin.

Many of the genes and proteins P63 activates are secreted factors and some of them contribute to inflammation. Indeed, researchers are exploring numerous ways inflammation might be exacerbating the progression of cancer.

P63 is also active in other types of cancer, including lung, head and neck cancers. Frequently, elevated levels of P63 in these other forms of cancer also lead to a worse prognosis.

Somerville explained that the changes P63 makes in a pancreatic cancer cell may expose new weaknesses. By studying cells in which he has overexpressed the protein, he hopes to see what other addictions the cells may have, which could include a reliance on other proteins that he could make compounds to target.

A resident of Huntington, Somerville has worked in Vakoc’s lab for three years. While he has spent considerable time studying P63, he is also looking at other transcription factors that are involved in pancreatic cancer.

Somerville wants to contribute to the discovery of why one form of pancreatic cancer is so much worse than the other. “If we can understand it, we can find new ways to stop it,” he said.

Originally from Manchester, England, Somerville is working in the United States on a five-year visa and plans to continue contributing to Vakoc’s lab for the next couple of years. At that point, he will consider his options, including a potential return to the United Kingdom.

Tim Somerville. Photo by Gina Motisi, 2018/CSHL

Somerville appreciates the opportunity to work on pancreatic cancer with Vakoc and with Tuveson, whose lab is next door. The researcher is enjoying his time on Long Island, where he takes walks, enjoys local restaurants and, until recently, had been playing on a Long Island soccer team, which played its matches in Glen Cove.

For Somerville, Cold Spring Harbor Laboratory has exceeded his high expectations. “The research that goes on here and the interactions you can have at meetings” have all contributed to a “great experience,” he said.

Somerville is excited to be a part of the pancreatic cancer team.

“With the work from [Tuveson’s] lab and ours, we’re finding new things we didn’t know,” he said. “It’s only when you understand those different things and the complexity that you can start thinking about how to tackle this in a more successful way. If the research carries on, we’ll make improvements in this disease.”