When it spreads, it becomes more difficult to treat. Understanding metastatic cancer presents significant challenges to doctors and scientists in part because the disease is different in the liver than it is in the lungs.

Lloyd Trotman, an associate professor at Cold Spring Harbor Laboratory, has created a mouse model of prostate cancer that becomes metastatic. By exploring what happens to cells in different areas, Trotman hopes to get a better understanding of cancer as it spreads.

“New technology allows us to tag cells when they are at the metastatic site,” he said. He can look at “how they differ from where they started.”

When prostate cancer becomes metastatic, the cells “forget about their identity,” Trotman said. They become more like cells that are developing, which means they are not as dependent on male hormones for their survival. This change in their identity makes them difficult to treat with hormone therapy.

By developing these metastatic models of prostate cancer, Trotman has been able to do preclinical studies of drugs designed to treat the original disease and its metastatic form. He has worked with scientists from Cornell University, the Dana-Farber Cancer Institute, and the Memorial Sloan Kettering Cancer Center.

“We can ask if a drug specifically is beneficial against metastatic cancer and especially against the hormone-refractory kind,” he said.
Trotman’s research also explores how cancers that were in remission become active again. “Most [treatments] will not be curative,” he said. “Why? If it works, but then the disease comes back, what is driving the disease? What is it that the drug is doing wrong at the point that it was looking good? What limit does the drug need to push to be curative?”

With his model of the disease, he can track the changes in a living animal. He can see how the cancerous cells are glowing in areas including the liver, lymph nodes, lungs, and bone. “Our hope is that by making these things visible at a very primitive level, we can see it first, then harvest it, and read the sequencing,” he said.

Trotman’s approach has won him the admiration of other scientists. “For an early career scientist, his work stands out as particularly innovative,” said Scott Lowe, a cancer biologist and chairman of the Geoffrey Beene Cancer Research Center at Memorial Sloan Kettering.
Lowe was deputy director of the cancer center at Cold Spring Harbor Laboratory, where he was involved in recruiting Trotman to join CSHL. “His research on an important cancer gene caught our attention,” Lowe said. He described Trotman as an “enthusiastic scientist who strives to address the most important questions in his field.”

Trotman explained that his goal isn’t just to understand how the genome works to cause cancer, but to figure out how to cure metastatic prostate disease. He wants to see where potentially effective drugs fail and to figure out what they should be doing differently. If he develops the kind of data he hopes to explore with the mouse, he would then argue that the same kind of analysis is necessary in humans, to make sure the model and the reality in humans are aligned.

While he’s focused on prostate cancer, Trotman said he would like to find a methodology that allows him to combat and understand cancer on a broader scale.

Born in the United States, Trotman moved to Switzerland when he was 2 years old. He attended high school and received his doctorate in Switzerland. He returned to New York to do his postdoctoral work at Sloan Kettering. He became a faculty member at Cold Spring Harbor Laboratory in 2007. Trotman’s Swiss background enabled him to become fluent in English, German, French and Swedish.

A resident of Oyster Bay, Trotman lives with his wife Eva Frosch, who runs the gallery Frosch & Portmann in New York City, and their sons Liam, 8, and Finn, 5.

Trotman loves summers on Long Island, where he can surf on the south shore and head to the beaches on the North Shore.
Trotman said he hopes his mouse model of prostate cancer can help uncover how cancer progresses, becomes metastatic, and resists drug treatment.

“There are many theories about how diseases like cancer evolve,” he said. His model can “help bring [the research] down to a level where everybody can see it.”

Paul Bingham and Zuzana Zachar, a husband-and-wife team at Stony Brook University, have spent the better part of a decade exploring a way to disrupt cancer’s energy supply line.

They have developed a compound that takes advantage of the different way cancer cells produce energy. With the help of other scientists at Stony Brook, including James Marecek in the Chemistry Department, they created another form of lipoate, called CPI-613, that doesn’t foster cancer growth.

“It’s like a Trojan horse,” explained Zachar, who is an assistant professor in the Department of Biochemistry and Cell Biology. “It has no catalytic ability,” which means that it looks like a key molecule for a cancer pathway in mitochondria, but doesn’t act like it.

By shutting down tumor cell mitochondria, the researchers are able to trigger several cell-death pathways selectively, explained Bingham, who is an associate professor in the same department. The scientists anticipate lower vulnerability to evolved resistance because the CPI-613 attacks two enzyme targets at the same time.

The Stony Brook team are in Phase II trials of this drug at Wake Forest University with patients who have leukemia and lymphoma.

“We saw a 38 percent response rate [among patients who were not responding to other therapies] in the first Phase I trial we completed” said Timothy Pardee, an assistant professor who conducted those trials and is performing a similar function in Phase II. While he believes the treatment has extended people’s lives, he cautioned that “it’s important to remember that these are very early results.”

The scientists have to generate significant evidence to be confident in their approach, both for basic science and for use with patients, Bingham said.

Even though the treatment has shown promise, it’s possible that cancers may respond to this approach the way they have to so many other treatments, by finding another way to avoid selective eradication. While the treatment the couple has worked on is designed to minimize this risk, they will only know whether they have been successful after extensive testing.

“Until we get more clinical experience, we can’t know that natural selection operating on cancer cells doesn’t have a diabolical trick we haven’t thought about,” Bingham said.

Robert Haltiwanger, the chairman of the Department of Biochemistry and Cell Biology, said scientists had known since the 1930’s that the metabolism of cancer cells is different from that of normal cells. Bingham and Zachar have developed a compound that “seems to have an effect,” which means it has potential in a “wide variety of cancers.” In addition to contributing to cancer research, Bingham is also a “very popular lecturer,” said Haltiwanger.

Bingham and Zachar, who had done extensive work on the fruit fly Drosophila, began looking at cancer metabolism in the late 1990’s as a “side project.” That showed enough promise for them to transform it into a full-time pursuit.

Bingham grew up in the rural Midwest, attending high school in a small town in a farming area of central Illinois that produces corn and soybeans. He received his doctorate from Harvard University in the Department of Biochemistry and Molecular Biology.

Zachar was born in what is now the Czech Republic. She moved to Ghana, West Africa when she was 10 and emigrated to the United States in 1968, settling near Chicago, Ill. She was at the University of North Carolina, Chapel Hill and Bingham was at the National Institute of Environmental Health Sciences in North Carolina when they met.

“We didn’t grow up as clinical researchers,” Bingham said. “We came up as basic, fundamental” scientists who were “drawn later in our careers into clinical work. When I was told we were going to work with people, my first reaction was anxiety for fear of doing harm.”

The researchers, who are residents of South Setauket and have lived on Long Island for 32 years, love the hiking trails.

They expressed satisfaction at the prospect of contributing to an effort that might aid in cancer treatment. Bingham said the research has particular meaning for him.

His mother, Doris Rorhman Bingham, died of cancer when he was 16. “Had she lived another 10 or 20 years, my life would have been completely different,” he said. “I still think of her almost every day.”

Zachar said the couple feel fortunate to be able to do this kind of work., “Saving other families from what [Bingham’s] family went through would be supremely fulfilling,” she said.

The human body not only defends itself against bacteria and viruses, but it also has a system to suppress or prevent tumors. Cancers, however, weaken this defense.

Sumita Bhaduri-McIntosh, an assistant professor in the Department of Pediatrics and in the Department of Molecular Genetics and Microbiology at Stony Brook University, has recently discovered a step cells take to weaken the cell’s defenses and become cancerous.

Using the Epstein-Barr virus, which causes mononucleosis and which more than 90 percent of people carry, Bhaduri-McIntosh has been able to turn healthy cells into those that divide and grow uncontrollably.

“If we take B cells (a part of the immune system) from healthy individuals and isolate those cells, we can infect them with EBV in the lab, where the virus expresses its own cancer,” she said. “This allows us to systematically examine a variety of cellular events, from minute one until we have these proliferating cells.”

Human cells have a defense called DNA damage response. This system is a set of mechanisms operating in every dividing cell that finds damage or defects in the genetic code and slows down or pauses the process of copying DNA and promotes repair of the damaged code, Bhaduri-McIntosh explained.

The virus she inserted triggered the activation and increased production of the cellular protein STAT3. Scientists knew this protein could drive gene expression and was an important ingredient in many human cancers. What they didn’t know, however, was that it also muted DNA damage response.

The results of these experiments were recently published in the journal the Proceedings of the National Academy of Sciences of the United States of America.

This finding “reveals a novel mechanism for development of cancer,” said Ayman El-Guindy, an assistant professor in the Division of Pediatric Infectious Diseases at Yale School of Medicine, where Bhaduri-McIntosh was a postdoctoral fellow and an assistant professor. Disruption of these pathways can “lead to accumulation of mutations in our genome that can ultimately cause cancer.”

El-Guindy suggested the kind of work Bhaduri-McIntosh is doing, while filled with the potential to help people, faces financial obstacles.

“While it is unfortunate that basic research is increasingly underfunded and has suffered multiple budget cuts in recent years, Dr. Bhaduri-Mcintosh’s discovery highlights the importance of basic research to develop new remedies against cancer,” El-Guindy said.

While a majority of people have the EBV, Bhaduri-McIntosh reassured people that it is extremely rare for it to become cancerous, especially in North America.

“There are EBV-related cancers that occur and are quite prevalent in other parts of the world,” including endemic Burkitt lymphoma in equatorial Africa, nasopharyngeal cell carcinoma in Southeast Asia and AIDS lymphomas.

Cancers caused by EBV can occur in as many as one in five solid-organ transplant recipients, triggered by the immunity-suppressing drugs that keep the recipient from rejecting the new organ.

A native of India, Bhaduri-McIntosh has a medical degree and a Ph.D. She sees patients as an attending physician at Stony Brook Children’s Hospital, although she spends most of her time doing research.

“When I was going through medical school in India, infectious disease is an even bigger scourge than in the western world,” she said. “You see it all around you, with tuberculosis, leprosy and parasitic diseases.” Studying infectious disease was “a very natural connection.”

Becoming an infectious disease expert “fed the detective urge,” she said, as symptoms don’t necessarily point to a specific diagnosis.

In one case when she was at Yale, she worked with a 10-year-old boy with multiorgan failure, while his bone marrow was making blood cells that were being destroyed. In an investigation of family members, she helped discover that some of them had a mutation.

The boy had a bone marrow transplant and, from the last she heard, “is doing rather well.”

Bhaduri-McIntosh credits her success to her parents in India and to her Wading River-based family. She and her husband, Michael McIntosh, the science adviser to the Foreign Animal Disease Diagnostic Laboratory on Plum Island, have a 14-year-old son, Rohin, and a 12-year-old daughter, Uma. She called the three of them “absolutely, veritable rocks.” She is also grateful for the support of the Pediatrics and Molecular Genetics departments.

When she’s not in the lab or helping patients, Bhaduri-McIntosh likes to sing. She was trained in Indian classical music. Nowadays, she sings Indian contemporary, as well as Western, music.

As for her career, working with patients and in research makes her better in both arenas, she said.

They know it works, but they’re not exactly sure how. They mix ingredients with something that helps make everything happen and, like a magician, wave their wand and get the rabbit, or in this case, the clean hydrogen, they were trying to produce. Except that, in their world, nature is the one whose slight of hand remains a mystery.

That’s where Argentinian-born Dario Stacchiola and his Brookhaven National Laboratory team of two postdoctoral researchers and one graduate student come in. An associate chemist, Stacchiola is trying to figure out the small steps in between the beginning of a reaction and the creation of this form of hydrogen, which is suitable for fuel cells in cars and industrial chemical processing.

While Stacchiola recognizes the possibility of a commercial use of his analysis down the road, he emphasizes that he is on a basic scientific mission. “Our end goal is not to get a commercial catalyst,” he said. “We are a step removed from that transition. We are really trying to look at the atomic level.”

Stacchiola’s curiosity about catalysts has earned him the admiration of his colleagues and coworkers. He is “well-respected not only across the lab, but also in our field,” said Ashleigh Baber, a postdoctoral researcher who has worked in his lab for three years.

His “knowledge of catalysis, coupled with his strength in experimental physical chemistry give him a unique perspective on how to approach and tackle important issues and holes in the field.”
Indeed, one of those many holes is understanding the intermediate reactions in the water-gas shift reaction, which is used to purify hydrogen and remove carbon monoxide.

“There are at least four different mechanisms proposed” for that reaction, Stacchiola said, with each one involving between five and 10 steps. His experiments helped to “narrow it down to two probable mechanisms.”

One of the big problems for scientists looking for these intermediate steps is that these reactions are easiest to see under cold, high-vacuum conditions, where the scientists don’t have to worry about interactions between the reactions they’re testing and atoms in the air. In those conditions, some of the intermediate chemicals generated during the reaction don’t form.

Using the latest technology, including near-ambient X-ray photoelectron spectroscopy, near-ambient pressure infrared reflection absorption spectroscopy, density functional theory computational analysis and scanning tunneling microscope, they were able to look behind the curtain in some of these steps at more everyday temperatures and pressures.

“We are now starting to see processes happen that we couldn’t see at lower pressures,” he said. He sees the stabilization of weak intermediates at the interface of oxide and metal nanoparticles in catalysts.

Scientists had predicted that the reactions Stacchiola studies would involve a carboxyl group, which is present in most organic acids and is made up of carbon, two oxygen atoms and hydrogen. These groups hadn’t been found on metal or oxide surfaces in this process. His research detected a product derived from the carboxyl group that was attached to the metal oxide interface of nanoparticles.

Scientists had predicted the likelihood of this carboxyl group for about a decade. The discovery of this combination of atoms was the closest thing to a “Eureka” moment he has had, Stacchiola said.

At conferences, Stacchiola has met with people who are trying to improve the efficiency of these reactions and who are looking to optimize the perimeter of oxide-metal interfaces.

Baber explained that “even small increases in catalytic efficiency extrapolate to huge savings in large-scale industrial processes.”
A resident of South Setauket, Stacchiola lives with his wife, Zulema Cabail, who does research and teaches microbiology at Stony Brook, and their 11-year-old daughter, Sofia, whose name, he said, is easy to reproduce in any language, which is helpful for a couple from Argentina who have lived in South America, Europe and North America.

As for his work, Stacchiola said he is driven by some of the same curiosities he had as a child, where he needed to understand how things worked. “I never felt very comfortable with black boxes,” he said.