Skip to Main Content

A Pressing Need for New Ideas for Pancreatic Cancer

February 25, 2021

“Try to think: What can I learn today?” Nita Ahuja, MD, MBA, FACS, often tells her students.

Dr. Ahuja, William H. Carmalt Professor and Chair of Surgery, takes her own advice as she searches for better ways to combat pancreatic cancer in her own lab. She is relatively new to Yale, having arrived in 2018, and since that time Yale Cancer Center has recruited a team of researchers who have formed the Yale Pancreatic Cancer Collaborative (YalePaCC) to create a collaboration of team science using the tools and expertise of various disciplines to improve success against pancreatic cancer—a mission they see as urgent.

Pancreatic cancer is currently the third leading cause of cancer deaths in the U.S. and is expected to soon become the second deadliest malignancy, surpassing colorectal cancer. In 1977, the five-year survival rate in pancreatic cancer was 2-3%. Today, it is only 10%, underlining the need for rapid progress.

Pancreatic cancer is so dangerous, in part, because it is often not detected until it is at an advanced stage. In addition, it does not respond as well as many other cancers to common treatments like chemotherapy. Dr. Ahuja has already discovered a biomarker that supports earlier detection of pancreatic cancer, and her search is not over. “Translational epigenetics and other forms of basic science research continue to advance our understanding of

pancreatic cancer. Our laboratories are on the frontlines of cancer research into biomarkers that could translate into precision diagnostics and therapeutics,” she said.

Despite poor outcomes nationally and internationally, patients do better when they receive treatment at places like Smilow Cancer Hospital, which is recognized by the National Pancreas Foundation as a Center of Excellence in pancreatic cancer, and where surgeons specialize in and treat a large number of these cancers. After completing a fellowship at Memorial Sloan Kettering Cancer Center, John Kunstman, MD, MHS, returned to Yale where he had done his surgical internship and residency. He was drawn back to New Haven to work with a former mentor, Ronald Salem, MD, FACS, FRSC (Ed), FRCS(C), MBChB, Lampman Professor of Surgery and “one of the most technically profound pancreatic surgeons I know.” Dr. Kunstman had a second reason for choosing to return: “Because it’s Yale Cancer Center, because it’s enmeshed in the university, which has an obviously outstanding research tradition and unparalleled research resources. I know as a clinician-scientist that it’s impossible for me to have success without collaborators across disciplines.”

In addition to his clinical work as a surgical oncologist, Dr. Kunstman conducts research in a number of areas. He is the principal investigator of the Yale Gastrointestinal Cancer Biorepository, which supports research projects throughout the cancer center (see related story). He also

studies premalignant cancerous lesions called intraductal papillary mucinous neoplasms (IPMN). “We know very little about why some develop into cancers and others never do,” Dr. Kunstman explained. His lab is currently working to develop cell lines that will make more IPMN research possible.

Like Dr. Kunstman, Luisa Escobar-Hoyos, PhD, came to Yale in part to work with other great scientists. “Yale is the Mecca of RNA biology,” she said. She is undertaking projects with renowned researchers Joan Steitz, PhD, Sterling Professor of Molecular Biophysics and Biochemistry, who has made groundbreaking discoveries about RNA, Karla Neugebauer, PhD, who directs the Yale Center for RNA Science and Medicine, and Susan Baserga, MD, PhD, who is making foundational discoveries connecting ribosome biogenesis to cancer.

For Dr. Escobar-Hoyos, who recently welcomed her first child, the fact that these world class scholars are also women, matters. “They understand how to continue your career, to have a life, and be a mom,” she said. Dr. Escobar- Hoyos’ research has uncovered the role of aberrant RNA splicing in immune response in both pancreatic and lung cancers. Her lab is currently testing a novel therapy, Splicing-Hit Oligonucleotide Therapy (SHOT), which aims to correct those splicing errors. The hope is that SHOT will be effective in tumors that are currently resistant to therapy, as tumors in the pancreas frequently are.

Procedures are already established to fix a splicing defect in the lab, but no one has solved the problem of delivering the therapy directly to a tumor cell. Dr. Escobar-Hoyos is now planning collaborations with Drs. Peter Glazer, Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics, and Donald Engelman, Eugene Higgins Professor of Molecular Biophysics and Biochemistry, who invented technology to deliver mRNA therapy to cells.

This kind of cross disciplinary collaboration is a key strategy of the YalePaCC, according to its Director Mandar Deepak Muzumdar, MD, Assistant Professor of Genetics and Medicine (Medical Oncology). Scientists highly trained in their individual disciplines need to learn to “speak a common language” in order to make these partnerships fruitful, he said. The collaborative helps to develop that capacity by hosting a seminar series together with the Center for Gastrointestinal Cancers, which hosts leading researchers from around the world to present their research in the fight against pancreatic cancer.

“Our unique ability to bring together clinicians and scientists focused on pancreatic cancer from throughout Yale and Smilow, and host regular concentrated discussions will propel the research endeavors and success in pancreatic cancer from Yale Cancer Center. I am proud of the collaborations already formed through YalePaCC and look forward to new advances from the team in the coming years,” said Pamela Kunz, MD, Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Associate Professor of Medicine (Medical Oncology). The Center for Gastrointestinal Cancers provides a foundation for the research efforts in all gastrointestinal cancers, including pancreatic cancer, and facilitates additional collaborations throughout the Cancer Center and Smilow.

Successful team science also requires a grant structure that supports collaborative work. “At Yale Cancer Center we have funding mechanisms in place to promote team science. As a result of the collaborative work, not only is positive progress seen in our surgical and clinical outcomes for pancreatic cancer, it is also evident in the abundance of federal funding for research and high impact publications which routinely come from Yale Cancer Center investigators,” said Dr. Ahuja.

The imperative to pool the clinical and intellectual resources of the Cancer Center, Smilow, and the university are obvious. In addition, patient involvement in research is essential. “I cannot be more grateful to the patient advocates,” said Dr. Escobar-Hoyos. Through her involvement in the Pancreatic Cancer Action Network, she has met many patients, whom she credits with working to increase federal funding. Those patients motivate her, she said, to find better treatments.

“The type of folks that generally care for patients with pancreatic cancer are those that enjoy a challenge but are also persistently curious,” said Dr. Kunstman. “I think we all wake up in the morning hoping that our career will substantially improve, not just the outcomes for our individual patients, but for all the patients who suffer from pancreatic cancer.”

Submitted by Emily Montemerlo on February 25, 2021