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Pancreatic Cancer

From left, Luisa Escobar-Hoyos, Lucia Roa and Ken Shroyer Photo by Cindy Leiton

By Daniel Dunaief

The prognosis and treatment for cancer varies, depending on the severity, stage and type of disease. With pancreatic ductal adenocarcinoma, the treatment options are often limited and the prognosis for most patients by the time doctors make a diagnosis is often bleak.

Researchers at the Renaissance School of Medicine’s Pathology Department at Stony Brook University have been testing for the presence of a protein called keratin 17, or K17, by staining tissue specimens or needle aspiration biopsy specimens. This measures the proportion of tumor cells that have high levels of expression.

This protein is typically active during embryological development or in stem cells, which are a type of cell that can differentiate into a wide range of other cells. It is also active in pancreatic cancer.

Ken Shroyer, department chairman; Luisa Escobar-Hoyos, assistant professor of pathology; and Lucia Roa, assistant professor of pathology recently published a paper in the journal Scientific Reports in which they documented how the level of this protein can indicate the prognosis for patients. K17 above a certain level typically suggests a worse prognosis.

The Stony Brook scientists want to understand why some pancreatic cancers are more aggressive than others, with the hope that they might be able to develop more effective ways to treat the most aggressive form of the disease.

In the recent research, the level of K17 not only indicated the prognosis for the most aggressive form of the disease, but it is also considered a “cause of making the tumors more aggressive,” Escobar-Hoyos added, which confirmed their previously published research and which unpublished data also supports.

Shroyer suggested that this research paper has been a validation of their plan to pursue the development of K17 as a way to differentiate one form of this insidious cancer from another.

While other cancers, such as cervical cancer, have proven quicker and easier to use K17 for its predictive power, the current work reflects the lab’s focus on pancreatic cancer. As such the research is a “great step forward to generate our first pancreatic cancer paper,” Shroyer said. His lab had previously published papers on other biomarkers in pancreatic cancer.

Escobar-Hoyos indicated that she and Shroyer anticipate that K17, which is one of a family of 54 different types of keratins in the human body, likely plays numerous roles in promoting cancer.

Indeed, K17 may promote the invasiveness of these cells, allowing them to spread from the original organ, in this case the pancreas, to other parts of the body. They are testing that concept through ongoing work in their lab.

The researchers believe that K17 may accelerate metastasis, but that line of thinking is “still at a relatively early stage,” Escobar-Hoyos said.

This protein may also change the metabolism of the cell. They believe K17 blocks the uptake of certain drugs by enhancing specific metabolic pathways. 

Additionally, K17 causes the degradation of p27, which is a tumor suppressor that controls cell division.

The researchers used two different ways to monitor the levels of protein, through mRNA analysis and through immunohistochemical localization. In the latter case, that involved staining the cells to look for the presence of the protein.

Roa, who is the first author on the paper, stained the slides and worked with Shroyer to score them.

The assistant professor, who came to Long Island with her daughter Laura who earned her bachelor’s degree and master’s in public policy at SBU, had been a pathologist and medical doctor when she lived in Colombia. She learned the IHC staining technique at Yale University just after she graduated from medical school and worked for six years as a postdoctoral fellow on several projects using IHC.

Roa is thrilled that she’s a part of a supportive team that could help develop techniques to improve patient diagnosis and care.

“We care deeply about developing a tool that will help us to treat patients and we value working together to accomplish this,” Roa explained in an email.

At this point, Shroyer and his team have identified key factors that cause K17 to be overexpressed. They are pursuing this line of research in the lab.

“We think K17 expression is dictated by something different than genetic status,” said Escobar-Hoyos. “This is speculation, but we think it might be triggered based on a patient’s immunity.”

After this study, the pathology team is looking to validate their results through different cohorts of patients. They are working with the Pancreatic Cancer Action Network and their scientific collaborators at Perthera Inc. to process tissue sections from these cases for K17 staining in their lab.

They are also at the early stages in the development of a collaboration with investigators at MD Anderson Cancer Center.

“If we can validate that K17 IHC testing is able to predict a response to the standard of care, then we’ll have permission to start a prospective analysis linked to a clinical trial,” Shroyer said.

Shroyer’s team is trying to understand how K17 becomes activated, what happens when they block that activation, and how it impacts the survival and tumor growth in animal models of pancreatic cancer.

In collaborations with other researchers, they are exploring how K17 impacts the therapeutic vulnerability of pancreatic cancer to over 2,000 FDA-approved compounds.

“There are a discrete list of compounds that are able to kill K17 positive cells,” Shroyer said. He is aiming to start phase 0 trials to validate the molecular model. If the data is sufficiently convincing, they can apply to the FDA to begin phase 1 trials.

He hopes this study is the first of many steps the lab will take in providing clues about how to diagnose and treat pancreatic cancer, which has been an intractable disease for researchers and doctors.

“This paper helps establish and confirm that K17 is an important and promising prognostic biomarker in pancreatic cancer,” Shroyer said. “For us, this is foundational for all the subsequent mechanistic studies that are in progress to understand how K17 drives cancer aggression.”

Dr. Minsig Choi and Paul Bingham. Photo from Stony Brook Medicine

By Daniel Dunaief

The Stony Brook Cancer Center is seeking patients with pancreatic cancer for a phase 3 drug trial of a treatment developed by a husband and wife team at SBU.

Dr. Minsig Choi. Photo from Stony Brook Medicine

Led by Minsig Choi, the principal investigator of the clinical trial and a medical oncologist at Stony Brook Cancer Center’s gastroenterology team, the study is part of a multicenter effort to test whether a drug known as CPI-613, or devimistat, can extend the lives of people battling against a form of cancer that often has a survival rate of around 8 percent five years after its discovery.

Paul Bingham. Photo from Stony Brook Medicine

Patients at Stony Brook will either receive the conventional treatment of FOLFIRINOX, or a combination of a FOLFIRINOX and CPI-613. An earlier study demonstrated a median survival of 20 months with the combination of the two drugs, compared with 11 months with just the standard chemotherapy.

“Pancreatic cancer is such a bad disease,” Choi said. “The overall survival is usually less than a year and life expectancy is very limited.”

Choi said the company that is developing the treatment, Rafael Pharmaceuticals, wanted Stony Brook to be a part of the larger phase 3 study because the drug was developed at the university. Indeed, Stony Brook is the only site on Long Island that is offering this treatment to patients who meet the requirements for the study.

People who have received treatment either from Stony Brook or at other facilities are ineligible to be a part of the current trial, Choi said. Additionally, patients with other conditions, such as cardiac or lung issues, would be excluded.

Additionally, the current study is only for “advanced patients with metastatic” pancreatic cancer, he said. People who have earlier forms of this cancer usually receive surgery or other therapies.

“When you’re testing new drugs, you want to start in a more advanced” clinical condition, he added.

Choi said patients who weren’t a part of the study, however, would still have other medical options.

Zuzana Zachar. Photo from Stony Brook Medicine

“The clinical trial is not the only way to treat” pancreatic cancer, he said. These other treatments would include chemotherapy options, palliative care, radiation therapy and other supportive services through social workers.

Choi anticipates that the current study, which his mentor Philip A. Philip, a professor in the Department of Oncology at the Barbara Ann Karmanos Cancer Institute in Detroit is leading, would likely provide preliminary results in the next 18 to 24 months.

If the early results prove especially effective, the drug may receive a fast-track designation at the Food and Drug Administration. That, however, depends on the response rate and the way patients tolerate the treatment.

At this point, Choi anticipates that most of the side effects will be related to the use of chemotherapy, which causes fatigue and weakness. The CPI-613, at least in preliminary studies, has been “pretty well tolerated,” although it, like other drug regimes, can cause upset stomachs, diarrhea and nausea, he said.

Doctors and researchers cautioned that cancer remains a problematic disease and that other drugs to treat forms of cancer have failed when they reach this final stage before FDA approval, in part because cancer can and often does develop ways to work around efforts to eradicate it.

Still, the FDA wouldn’t have approved the use of this drug in this trial unless the earlier studies had shown positive results. Prior to this broader clinical effort, patients who used CPI-613 in combination with FOLFIRINOX had a tumor response rate of 61 percent, compared with about half that rate without the additional treatment.

Paul Bingham, an associate professor in the Department of Biochemistry and Cell Biology at Stony Brook University, and his wife Zuzana Zachar, a research assistant professor and director of Master in Teaching Biology Program at the Institute for STEM Education at Stony Brook, originally invented and discovered the family of drugs that includes CPI-613.

Bingham and Zachar, who are consultants to Rafael Pharmaceuticals, “provide basic scientific support” in connection with this phase 3 trial. “When the FDA asks questions, sometimes it requires us to do basic science” to offer replies, he said.

Zachar and Bingham developed this drug because they anticipated that attacking cancer cell’s metabolism could lead to an effective treatment. Cancer requires considerable energy to continue on its deadly course. This drug, which is a lipoate analog and is an enzyme cofactor in several central processes in metabolism, tricks the disease into believing that it has sufficient energy. Interrupting this energy feedback mechanism causes the cancer cell to starve to death. 

While other cells use some of the same energy feedback pathways, they don’t have the same energy demands and the introduction of the drug, which has tumor-specific effects, is rarely fatal for those cells.

The lipoate analog is a “stable version of the normally transient intermediary that lies to the regulatory systems, which causes them to shut down the metabolism of cancer cells,” Bingham said. These cells “run out of energy.”

Zachar said the process of understanding how CPI-613 could become an effective treatment occurred over the course of years and developed through an “accretion of data that starts to fill in a picture and eventually you get enough information to say that it could be” a candidate to help patients. The process is more “incremental than instantaneous.”

Bingham and Zachar are working on a series of additional research papers that reflect the way different tumors and tumor types have different sensitivities to CPI-613. They expect to publish at least one new paper this year and several more next year.

The researchers who developed this drug have had some contact with patients through the process. While they are not doctors, they are grateful that the work they’ve done has “extended and improved people’s lives,” Bingham said, and they are “grateful for that opportunity.”

Zachar added that she is “thrilled that we’ve been able to help.” She appreciates the contribution the patients make to this research because they “stepped to the line and took the risk to try this drug.”

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‘Jeopardy!’ host Alex Trebek, left, pictured with former contestant Kevin Foley of Mount Sinai, has been diagnosed recently with pancreatic cancer. Photo from Alex Foley

By Anthony Frasca

After multiple Emmy award-winning “Jeopardy!” host, Alex Trebek, announced that he had stage 4 pancreatic cancer, the news has drawn attention to the disease and raised questions related to the latest advances in diagnosis and treatment of pancreatic cancer.

Dr. Aaron Sasson, director of the Pancreatic Cancer Center at Stony Brook University and chief of the Surgical Oncology Division, said little has changed when it comes to a doctor’s ability to diagnose the cancer any earlier.

“But we have made improvements in imaging of pancreatic cancer,” he said. “That is, the quality of CT scans and MRIs has improved over the years.”

Kerri Kaplan, president and CEO of the Lustgarten Foundation, said the disease has been “notoriously difficult” to detect and treat. The organization is dedicated to pancreatic cancer research.

“Although great strides are being made to detect pancreatic cancer earlier, this disease has few warning signs and vague symptoms that may range from back pain, fatigue and loss of appetite, amongst others,” she said in an email.

Kaplan added, “Even when there are early signs and symptoms, they may easily be attributed to other illnesses. Because of this, patients are often diagnosed when the cancer is at an advanced stage or has spread to other organs — making them ineligible to undergo surgery, which is the best chance at long-term survival.”

According to the foundation, pancreatic cancer research is moving faster than ever before. The nonprofit is funding a range of innovative projects including artificial intelligence in a partnership with Pancreatic Cancer Collective to use computational approaches to identifying high-risk pancreatic cancer populations, and CancerSEEK, which is an early detection initiative that uses blood testing to identify eight different types of cancer including pancreatic cancer.

Other Lustgarten projects include Dr. David Tuveson of Cold Spring Harbor Laboratory leading a personalized approach to medicine called organoids for personalized therapy — a three-dimensional cell culture system which reproduces a patient’s tumor to test it repeatedly with different drugs. This approach will enable researchers to determine how a pancreatic cancer patient will respond to various treatments. And with an improved imaging and early detection project, scientists from a broad range of disciplines focus on the use of computers to recognize patterns in medical imaging with the goal of finding tumors when they are otherwise undetectable by the human eye.

Also, as a result of Lustgarten-funded research, the U.S. Food & Drug Association recently approved Keytruda as the first immunotherapy treatment for advanced pancreatic cancer patients whose tumors have a unique genetic mutation.

“In the last 10 years our understanding of pancreatic cancer has significantly improved,” Sasson said. “I think we are on the cusp of something remarkable in the next couple of years coming out with regards to treatment. Our understanding of the genetics the biology and immunotherapy of pancreatic cancer, all those things are going to be realized, I’m hopeful, in the next couple of years.”

The five-year survival rate for pancreatic cancer is 9 percent according to the American Cancer Society. Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Improvements in survival rates for pancreatic cancer are challenging because nearly half of the cancers are not detected until they are in advanced stages.

Photo by Ela Elyada

By Daniel Dunaief

What if, instead of defeating or removing enemy soldiers from the battlefield, a leader could convince them to join the fight, sending them back out to defeat the side they previously supported? That’s the question Giulia Biffi, a postdoctoral researcher at Cold Spring Harbor Laboratory, is asking about a particular type of cells, called fibroblasts, that are involved in pancreatic cancer.

Fibroblasts activated by cancer cells secrete a matrix that surrounds cancer cells and makes up about 90 percent of pancreatic tumors.

Giulia Biffi. Photo by ©Gina Motisi, 2018/CSHL

Responding to a molecule called IL-1, an inflammatory potential tumor-promoting fibroblast may enhance the opportunity for cancer to grow and spread. Another type of fibroblast responds to TGF-beta, which potentially enables them to restrain tumors.

Researchers had suggested that the inflammatory fibroblasts are tumor promoting, while the myofibroblasts are tumor defeating, although at this point, that still hasn’t been confirmed experimentally.

Researchers knew TGF-beta was important in biology, but they didn’t know that it was involved in preventing the activation of an inflammatory tumor-promoting version.

Biffi, however, recently found that IL-1 promotes the formation of inflammatory fibroblasts. She believes these fibroblast promote tumor growth and create an immunosuppressive environment.

In an article published in the journal Cancer Discovery, Biffi showed that it’s “not only possible to delete the population, but it’s also possible to convert [the fibroblasts] into the other type, which could be more beneficial than just getting rid of the tumor-promoting cells,” she said.

Biffi works in Director Dave Tuveson’s CSHL Cancer Center laboratory, which is approaching pancreatic cancer from numerous perspectives.

Her doctoral adviser, Sir Shankar Balasubramanian, the Herchel Smith Professor of Medicinal Chemistry at the University of Cambridge, suggested that the work she did in Tuveson’s lab is an extension of her successful research in England.

“It is evident that [Biffi] is continuing to make penetrating and important advances with a deep and sophisticated approach to research,” Balasubramanian explained in an email. “She is without a doubt a scientist to watch out for in the future.”

To be sure, at this stage, Biffi has performed her studies on a mouse model of the disease and she and others studying fibroblasts and the tumor microenvironment that dictates specific molecular pathways have considerable work to do to extend this research to human treatment.

She doesn’t have similar information from human patients, but the mouse models show that targeting some subsets of fibroblasts impairs cancer growth.

“One of the goals we have is trying to be able to better classify the stroma from pancreatic cancer in humans,” Biffi said. The stroma is mixed in with the cancer cells, all around and in between clusters of cells.

The results with mice, however, suggest that approaching cancer by understanding the molecular signals from fibroblasts could offer a promising additional resource to a future treatment. In a 10-day study of mice using a specific inhibitor involved in the pathway of inflammatory fibroblasts, Biffi saw a reduction in tumor growth.

If Biffi can figure out a way to affect the signals produced by fibroblasts, she might be able to make the stroma and the cancer cells more accessible to drugs. One potential reason other drugs failed in mouse models is that there’s increased collagen, which is a barrier to drug delivery. Drugs that might have failed in earlier clinical efforts could be reevaluated in combination with other treatments, Biffi suggested, adding if scientists can manage to target the inflammatory path, they might mitigate some of this effect.

A native of Bergamo, Italy, which is near Milan, Biffi earned her doctorate at the Cancer Research UK Cambridge Institute. Biffi lives on a Cold Spring Harbor property which is five minutes from the lab.

When she was young, Biffi wanted to be a vet. In high school, she was fascinated by the study of animal behavior and considered Dian Fossey from “Gorillas in the Mist” an inspiration. When she’s not working in the lab, she enjoys the opportunity to see Broadway shows and to hike around a trail on the Cold Spring Harbor campus.

Biffi started working on fibroblasts three years ago in Tuveson’s lab. “I really wanted to understand how fibroblasts become one population or the other when they were starting from the same cell type,” she said. “If they have different functions, I wanted to target them selectively to understand their role in pancreatic cancer to see if one might have a tumor restraining role.”

A postdoctoral researcher for over four years, Biffi is starting to look for the next step in her career and hopes to have her own lab by the end of 2019 or the beginning of 2020.

When she was transitioning from her doctoral to a postdoctoral job, she was looking for someone who shared her idealistic view about curing cancer. Several other researchers in Cambridge suggested that she’d find a welcome research setting in Tuveson’s lab. Tuveson was “popular” among principal investigators in her institute, Biffi said. “I wanted to work on a hard cancer to treat and I wanted to work with [Tuveson].”

Biffi hopes that targeting the inflammatory pro-tumorigenic fibroblasts and reprogramming them to the potentially tumor-restraining population may become a part of a pancreatic cancer treatment.

She remains optimistic that she and others will make a difference. “This can be a frustrating job,” she said. “If you didn’t have hope you can change things, you wouldn’t do it. “I’m optimistic.”

Biffi points to the hard work that led to treatments for the flu and for AIDS. “Years back, both diseases were lethal and now therapeutic advances made them manageable,” she explained in an email. “That is where I want to go with pancreatic cancer.”

Aaron Sasson. Photo courtesy of Stony Brook Medicine

By Daniel Dunaief

Thanks to the efforts of Stony Brook University School of Medicine’s Chief of Surgical Oncology Aaron Sasson and numerous doctors and researchers at Stony Brook, Long Island has its first National Pancreas Foundation Center.

A nonprofit organization, the National Pancreas Foundation goes through an extensive screening process to designate such centers around the country, recognizing those that focus on multidisciplinary treatment of pancreatic cancer. The NPF offers this distinction to those institutions that treat the whole patient and that offer some of the best outcomes and improved quality of life for people suffering with a disease who have an 8 percent survival rate five years after diagnosis.

Sasson appreciates the team effort at the medical school. “As opposed to one person leading this, there are many people here who are required to have an interest in pancreatic cancer,” he said. “We are not only looking to build a great infrastructure for the treatment of pancreatic cancer, but we’re also looking to build a team for research on pancreatic cancer.”

Sasson highlighted the research efforts led by Yusuf Hannun, the director of the Cancer Center at SBU, who has helped attract a “tremendous number of scientists” to engage in research into this disease.

The recognition by the NPF helps the university recruit physicians who are clinically interested in developing ways to improve the outcome for patients.

Pancreatic cancer presents particular challenges complicated by its biological aggressiveness, its difficulty to detect and by the many subtypes of this disease. “It’s similar to lung and breast cancer,” Sasson said. “There are many facets of those cancers. You can’t lump them all together.”

Researchers and clinicians are still trying to understand pancreatic cancer in greater detail. Once they have done that, they can advance to treating the possible subtypes.

Numerous researchers at SBU have developed collaborations with scientists at Cold Spring Harbor Laboratory. David Tuveson, the director of the National Cancer Institute-designated Cancer Center, has engaged in collaborations with SBU scientists in his work on organoids, which are model human organs grown in a lab. Scientists use organoids to test drugs and molecular pathways involved in pancreatic cancer.

Members of the Long Island community can take comfort in the continuing dedication of the numerous staff members committed to finding a cure. “Residents of Suffolk County and Long Island should be proud of what Stony Brook has been able to accomplish,” Sasson said.

Stony Brook University has been involved in several clinical efforts. The university developed a drug called CPI-613, for which Rafael Pharmaceuticals is in the early stage of clinical trials in combination with other drugs.

In early stages, the treatment increases the vulnerability of cancer cells to numerous other drugs. Newark, New Jersey-based Rafael Pharmaceuticals is testing this treatment in pancreatic cancer and in acute myeloid leukemia.

At SBU facilities, Sasson explained that researchers and clinicians are taking a multidisciplinary approach in their work. One study, he said, is exploring the effects of a kind of radiation therapy for a subpopulation of pancreatic cancer that combines expertise in radiology, gastroenterology, pathology and medical and surgical oncology.

Sasson himself is interested in screening and biomarkers. At least half of his work is related to pancreatic cancer. When he thinks about people who have battled pancreatic cancer, several patients come to mind. He had a patient who was about 80 at the time of his diagnosis. His primary doctor told him to get his affairs in order.

“We operated on him and he lived another six or seven years,” Sasson recalls. “He was grateful to see his grandchildren graduate and to see his great-grandbabies being born.”

While every patient is unlikely to have the same outcome, Sasson said surrendering to the disease and preparing for the inevitable may not be the only option, as there may be other courses of action.

Another patient had advanced pancreatic cancer for 18 months before Sasson met her. She had received no treatment and yet the cancer didn’t progress, which is “almost unheard of and unbelievable.” In fact, the case defied medical expectations so dramatically that the doctors conducted two more biopsies to confirm that she had pancreatic cancer. “She did well for many years despite having advanced pancreatic cancer.”

In another case, a patient was receiving surveillance for lung cancer every three months. In between those visits, he had developed metastatic pancreatic cancer. This patient example and the previous one show the range of cancer progression.

The value of having an integrated clinical and research program is that scientists can look for subtle clues and signals amid the reality of cancer with a wide range of outcomes. Indeed, scientists attend the weekly tumor board meeting, so they can learn about the clinical aspects of the disease. Doctors also attend research collaborations so they can hear about developments in the lab.

Rather than dictating how researchers and clinicians should collaborate, Sasson hopes to facilitate an environment that sparks these partnerships.

Sasson joined Stony Brook Medical School almost three years ago. He said he is “impressed with the caliber of physicians.” It took time to get the critical mass and organization for pancreatic cancer to match the number of basic science investigators.

“I’m hopeful for the progress we’ll be able to make to treat this terrible disease,” he said.

Port Jefferson Village snatched ownership of the Village Cup back from John T. Mather Memorial Hospital at the 7th annual Village Cup Regatta boat race on Sept. 10 in Port Jefferson Harbor.

The race, which is presented by the Port Jefferson Yacht Club, features about a dozen competing boats representing either the village or Mather Hospital, and is held for a good cause.

The event has raised more than $300,000 since its inception for Mather’s Palliative Medicine Program and the Lustgarten Foundation, which funds pancreatic cancer research.

The hospital held the cup entering the 2016 race, though the village has now won four of the last six years.

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Port Jefferson Yacht Club hosted its sixth annual Village Cup Regatta on Saturday, raising funds for pancreatic cancer research through the Lustgarten Foundation and for John T. Mather Memorial Hospital’s palliative medicine program.

The regatta pits the hospital and Port Jefferson Village against one another in a friendly competition for the Village Cup, a trophy which the hospital has now won two years in a row following a village reign of three years.

Participants raised about $64,000 for the cause through this year’s race, according to yacht club member Chuck Chiaramonte. The sum will be split between the Lustgarten Foundation and the palliative care program, which is focused on improving patients’ quality of life.

Chiaramonte said over the six years of the regatta, the event has raised more than $300,000.

The yacht club — formerly known as the Setauket Yacht Club — supplied the boats and captains for the event, which included a parade of boats, games and face painting for children at the harborfront park, and a trophy presentation at the adjacent Village Center.

Chiaramonte said the club looks forward to the event every year.

“It was really meant to just be a joyous occasion and share the love of the water and boating with our neighbors,” he said.