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Luisa Escobar-Hoyos

Kenneth Shroyer and Luisa Escobar-Hoyos are the recent recipients of a two-year research grant from PanCAN. Photo by Cindy Leiton

By Daniel Dunaief

Stony Brook University has collected its first PanCAN award. Pathology Chair Kenneth Shroyer and Assistant Professor and Co-Director of the Pathology Translational Research Lab Luisa Escobar-Hoyos have earned a two-year $500,000 research grant from the Pancreatic Cancer Action Network.

The tandem has worked together for seven years on the protein keratin 17, or k17, which started out as an unlikely participant in pancreatic cancer and as a molecule cancer uses to evade chemotherapy.

Shroyer and Escobar-Hoyos were “thrilled to get the award,” said Shroyer in a recent email. “While we thought our proposal was very strong, we knew that this was a highly competitive process.”

Indeed, the funding level for the PanCAN grants program was between 10 and 15 percent, according to PanCAN.

The grants review committee sought to identify projects that “would constitute novel targets for treating pancreatic cancer,” said Maya Bader, the associate director of scientific grants at PanCAN. 

“Given that k17 represents a potential new target, the committee felt the project was a good fit with exciting potential to meet this goal. We are thrilled to welcome Dr. Shroyer to the PanCAN grantee research community and look forward to following both his and Dr. Escobar-Hoyos’ contributions to the field,” she said.

Escobar-Hoyos explained that she and Shroyer hope “this work will shed scientific insight into potential novel ways to treat the most aggressive form of pancreatic ductal adenocarcinoma,” which is the most common type of pancreatic cancer.

Although they are not sure if their approaches will be successful, she believes they will provide information that researchers can use to “further understand this aggressive disease.”

Thus far, Shroyer and Escobar-Hoyos have focused on the role of k17 in pulling the tumor suppressor protein p27 out of the nucleus into the cytoplasm, where it is degraded. More recently, however, they have explored how the k17 the tumor produces reprograms the cancer metabolome.

They have data that suggests that k17 impacts several dozen proteins, Escobar-Hoyos suggested. If the tumors of patients express k17, around half the protein content will go to the nucleus of the cell. 

In addition to understanding what k17 does when it enters the nucleus, Escobar-Hoyos and Shroyer are testing how they might stop k17 from entering the nucleus at all. Such an approach may prevent pancreatic cancer from growing.

Shroyer and Escobar-Hoyos are working with a graduate student in the lab, Chun-Hao Pan, who is testing molecular pathways that might make pancreatic cancer more resistant to chemotherapy.

Dr. Yusuf Hannun, the director of the Stony Brook Cancer Center, was pleased that his fellow Stony Brook scientists earned the PanCAN distinction.

“It is an important award and speaks to our growing significant efforts in research in pancreatic cancer,” he said, suggesting that the research could have important benefits for patients battling with pancreatic cancer.

“This defines at the very least a novel and important biomarker for pancreatic cancer that can also extend into novel therapeutic approaches,” Hannun said. This type of research could enhance the diagnostic process, allowing doctors to subtype pancreatic cancers and, if the pathways become clearer, enhance the effect of chemotherapy.

The funds from the PanCAN award will support experiments in cell culture and in animal models of pancreatic cancer, Shroyer explained.

Shroyer has teamed up with numerous researchers at Stony Brook and Cold Spring Harbor Laboratory on this work.

As proof of principle for one aspect of the proposal, he accessed chemosensitivity data from pancreatic cancer organoids. Hervé Tiriac, a research investigator who works in David Tuveson’s lab at CSHL, generated these organoids from SBU pancreatic cancer specimens.

In addition to their work with organoids at CSHL, Shroyer and Escober-Hoyos benefited from their collaboration with SBU’s Ellen Li, a professor of medicine, who ensured patient consent and specimen collection.

Going forward at Stony Brook University, the key collaborator for this project will be Richard Moffitt, an assistant professor in the departments of Biomedical Informatics and Pathology.

Shroyer described Moffitt as an “internationally recognized leader in the field of pancreatic cancer subtyping” who is working to understand better how k17 could serve as a prognostic biomarker.

At the same time, Wei Hou from the Department of Family, Population and Preventive Medicine will provide biostatistical support throughout the course of the project.

PanCAN, which has donated $48 million to support pancreatic cancer research, awarded nine grants this year in the United States, Canada and France, for a total contribution of $4.2 million. 

The other scientists include Andrew Aguirre from the Dana-Farber Cancer Institute, Scott Lowe, who had previously worked at Cold Spring Harbor Laboratory and is now at Memorial Sloan-Kettering Cancer Center and George Miller at New York University School of Medicine.

Previous recipients of PanCAN awards have been able to leverage the funds to attract research dollars to their work.

Grantees who had received $28.2 million from 2003 to 2015 went on to receive $311 million in subsequent funding to support their pancreatic cancer research, according to PanCAN. That means that every dollar awarded by PanCAN converts to $11.01 to fund future research aimed at understanding, diagnosing and treating pancreatic cancer, according to Bader. Most of the subsequent funding comes from government sources.

PanCAN award recipients have published research that other scientists have cited more than 11,000 times in other papers published in biomedical journals. This means “other researchers are reading, learning from and building upon our grantees’ work,” Bader added.

Daniel Mockler in his office at Stony Brook University. Photo from SBU

By Daniel Dunaief

At first, people didn’t believe it. Now, it seems, they are eager to learn more.

Working with a talented team that included postdoctoral researchers, doctoral students and doctors, Kenneth Shroyer, the chairman of the Department of Pathology at Stony Brook University, noticed something odd about a protein that scientists thought played a supporting role, but that, as it turns out, may be much more of a villain in the cancer story.

Known as keratin 17, this protein was thought to act as a tent pole, providing structural support. That, however, isn’t the only thing it can do. The co-director of Shroyer’s lab, Luisa Escobar-Hoyos, found that this protein was prevalent in some types of cancers. What’s more, the protein seemed to be in higher concentration in a more aggressive form of the disease.

Now, working with Long Island native Daniel Mockler, a clinical assistant professor in the Department of Pathology, Shroyer and his team discovered that the presence of this particular protein has prognostic value for endocervical glandular neoplasia, suggesting the likely course of the disease.

Published in the American Journal of Clinical Pathology, the article by Mockler and his team in the Sept. 1, 2017, issue attracted the attention of pathologists around the world. It ranked as the third highest read article in the final month of 2017, according to Medscape. It was behind two other papers that were review articles, which made it the most read primary research report in pathology in December.

The response “did exceed my expectations,” Mockler stated in an email. “I would have thought [Shroyer’s earlier] paper showing that k17 can function in gene regulation would have been more popular. But I guess this [new paper] illustrates that topics that have a possible direct impact on practicing surgical pathologists will draw a lot of attention.”

To be sure, while the recent study is an early indication of the potential predictive value of this protein, there may be some mitigating factors that could affect its clinical applicability.

“It’s premature to know what the clinical utility of this marker will be,” Shroyer said. “To determine that would require a large-scale prospective clinical trial” that would involve other patient populations and other laboratories.

Still, depending on the outcome of research currently underway in Shroyer’s lab, the protein may offer a way of determining the necessary therapy for patients with the same diagnosis.

Doctors don’t want to give patients with milder version of the disease high levels of chemotherapy, which would cause uncomfortable side effects. At the same time, they want to be as aggressive as possible in treating patients whose cancers are likely a more significant threat.

“The goal of having an excellent prognostic biomarker … is to avoid over and under treatment of patients,” suggested Mockler, who is also an attending pathologist at SBU and Stony Brook Southampton.

Shroyer was delighted with the efforts of the team that put together this well-read research. “As is true of all our clinical faculty, I want to give them every opportunity to take advantage of their ability to collaborate with research faculty in our department and throughout the cancer center and the school of medicine to advance their scholarly careers and academic productivity,” he said.

Mockler’s success and the visibility of this paper is “an excellent example of how someone with a busy clinical practice can also have a major impact on translational research,” Shroyer added.

Mockler appreciated the support and work of Escobar-Hoyos, who had conducted her doctoral research in Shroyer’s lab. She has “been the main driving force, along with [Shroyer] in the initial discovery of k17 including its prognostic implications as well as its possible function in regulating gene expression,” he said.

Mockler said he spends about 80 percent of his time on patient care, with the remaining efforts divided between research and academic pursuits. His first priority is providing “excellent patient care.”

Working with Shroyer and Escobar-Hoyos, Mockler explained that they have started looking at k17 in organ systems including the esophagus, pancreas and bladder. “We are currently looking at k17 from a diagnostic point of view in regards to bladder cancer,” he said. “Discoveries that impact the daily signout of surgical pathologists by allowing us to make better and more consistent diagnoses interests me very much.”

A resident of Kings Park, Mockler, who grew up in Hicksville, lives with his fiancée Danielle Kurkowski, who is a medical technologist of flow cytometry research and development at ICON Central Laboratories in Farmingdale.

Daniel Mockler on a recent snowboarding trip to Aspen. Photo from Daniel Mockler

Outside of his work in medicine, Mockler is an avid snowboard enthusiast. He tries to get in as many trips as possible during the winter, including a vacation a few weeks ago to the Austrian Alps. A more typical trip, however, is to western mountains or to Vermont, including Killington, Okemo and Stratton.

“To blow off steam and relax, nothing is better than being on a snow-covered mountain,” he said.

Mockler is pleased with the developments in the department. He has seen the “research goals of the department change quite significantly,” adding that Shroyer has “done a tremendous amount of recruiting.”

Mockler suggests to residents that it’s “good to get involved. I always tell them that [Shroyer] has a pretty active research lab and he likes it when residents get involved.”

As for his work on k17, Mockler is pleased that he’s been able to contribute to the ongoing efforts. Shroyer “has been doing this a while and I have seen the excitement and energy he has put into k17,” he explained, “so I know that we are onto something big.”

And so, apparently, do readers of pathology journals.

Escobar-Hoyos, center, holds her recent award, with Kenneth Shroyer, the chairman of the Department of Pathology at Stony Brook on the left and Steven Leach, the director of the David M. Rubenstein Center for Pancreatic Cancer Research on the right. Photo by Cindy Leiton

By Daniel Dunaief

While winter storm Niko in February closed schools and businesses and brought considerable precipitation to the region, it also coincided with great news for Luisa Escobar-Hoyos, who earned her doctorate from Stony Brook University.

Escobar-Hoyos, who is a part-time research assistant professor in the Department of Pathology at Stony Brook University and a postdoctoral fellow at Memorial Sloan Kettering Cancer Center, received word that she was the sole researcher selected in the country to receive the prestigious $600,000 Pancreatic Cancer Action Network–American Association for Cancer Research Pathway to Leadership Award.

When she heard the news, Escobar-Hoyos said she was “filled with excitement.” After she spoke with her husband Nicolas Hernandez and her current mentor at MSKCC, Steven Leach, the director of the David M. Rubenstein Center for Pancreatic Cancer Research, she called her parents in her native Colombia.

Her mother, Luz Hoyos, understood her excitement not only as a parent but as a cancer researcher herself. “My interest in cancer research started because of my mom,” Escobar-Hoyos said. Observing her example and “the excitement and the impact she has on her students and young scientists working with her, I could see myself” following in her footsteps.

The researcher said her joy at winning the award has blended with “a sense of responsibility” to the growing community of patients and their families who have developed a deadly disease that is projected to become the second leading cause of cancer-related death by 2020, according to the Pancreatic Cancer Action Network, moving past colorectal cancer.

The Pancreatic Cancer Action Network has awarded $35 million in funding to 142 scientists across the country from 2003 to 2016, many of whom have continued to improve an understanding of this insidious form of cancer.

David Tuveson, the current director of the Cancer Center at Cold Spring Harbor Laboratory, received funds from PanCan to develop the first genetically engineered mouse model that mimics human disease. Jiyoung Ahn, the associate director of the NYU Cancer Institute, used the funds to discover that two species of oral bacteria are associated with an over 50 percent increased risk of pancreatic cancer.

Over the first decade since PanCan started awarding these grants, the recipients have been able to convert each dollar granted into $8.28 in further pancreatic cancer research funding.

In her research, Escobar-Hoyos suggests that alternative splicing, or splitting up messenger RNA at different locations to create different versions of the same protein, plays an important part in the start and progress of pancreatic cancer. “Her preliminary data suggest that alternative splicing could be associated with poorer survival and resistance to treatment,” Lynn Matrisian, the chief science officer at PanCan, explained in an email. “The completion of her project will enhance our understanding of this molecular modification and how it impacts pancreatic cancer cell growth, survival and the progression to more advanced stages of this disease.”

Escobar-Hoyos explained that she will evaluate how mutations in transcriptional regulators and mRNA splicing factors influence gene expression and alternative splicing of mRNAs to promote the disease and aggression of the most common form of pancreatic cancer. Later, she will evaluate how splicing regulators and alternatively spliced genes enriched in pancreatic ductal adenocarcinoma contribute to tumor maintenance and resistance to therapy.

Escobar-Hoyos will receive $75,000 in each of the first two years of the award to pay for a salary or a technician, during a mentored phase of the award. After those two years, she will receive $150,000 for three years, when PanCan expects her to be in an independent research position.

Escobar-Hoyos said her graduate research at Stony Brook focused on ways to understand the biological differences between patients diagnosed with the same cancer type. She helped discover the way a keratin protein called K17 entered the nucleus and brought another protein into the cytoplasm, making one type of tumor more aggressive.

While Escobar-Hoyos works full time at Memorial Sloan Kettering, she continues to play an active role in Kenneth Shroyer’s lab, where she conducted experiments for her doctorate. She is the co-director of the Pathology Translational Research Laboratory, leading studies that are focused on pancreatic cancer biomarkers. The chair in the Department of Pathology, Shroyer extended an offer for her to continue to address the research questions her work addressed after she started her postdoctoral fellowship.

“When you do research projects and you develop them from the beginning, they are like babies and you really want to see how they evolve,” Escobar-Hoyos said. Numerous projects are devoted to different aspects of K17, she said.

Shroyer said Escobar-Hoyos had already been the first author on two landmark studies related to the discovery and validation of K17 even before her work with pancreatic cancer. “She has also conducted highly significant new research” that she is currently developing “that I believe will transform the field of pancreatic cancer research,” Shroyer wrote in an email.

Shroyer hopes to recruit Escobar-Hoyos to return to Stony Brook when she completes her fellowship to a full-time position as a tenure track assistant professor. “Based on her achievements in basic research and her passion to translate her findings to improve the care of patients with pancreatic cancer, I have no doubt she is one of the most promising young pancreatic cancer research scientists of her generation,” he continued.

Yusuf Hannun, the director of the Stony Brook Cancer Center, said Escobar-Hoyos’s work provided a new and important angle with considerable promise in understanding pancreatic cancer. “She is a tremendous example of success for junior investigators,” Hannun wrote in an email.

Escobar-Hoyos said she is hoping, a year or two from now, to transition to becoming an independent scientist and principal investigator, ideally at an academic institution. “Because of my strong ties with Stony Brook and all the effort the institution is investing in pancreatic research” SBU is currently her first choice.

Escobar-Hoyos is pleased that she was able to give back to the Pancreatic Cancer Action Network when she and a team of other friends and family helped raise about $4,000 as a part of a PurpleStride 5K walk in Prospect Park earlier this month.“I was paying forward what this foundation has done for me in my career,” she said.

Matrisian said dedicated scientists offer hope to patients and their families. “Researchers like Escobar-Hoyos spark scientific breakthroughs that may create treatments and ultimately, improve the lives of patients,” she suggested.

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