Predicting chemotherapy response and tailoring treatments for pancreatic cancer patients

LEBANON, NH – By 2030, pancreatic ductal adenocarcinoma (PDAC), the most lethal form of pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the United States. Not only are therapeutic options limited, but nearly half of all PDAC patients who have their tumors removed surgically experience disease recurrence within a year, despite receiving additional chemotherapy. For more advanced stages, only about one-third of patients have a limited response to approved chemotherapy.

A team of researchers led by Dartmouth and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC) Director Steven D. Leach, MD, and Surajit Dhara, PhD, Senior Research Scientist in the Leach laboratory, in collaboration with colleagues at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, are developing the first prognostic and therapeutic epigenetic biomarker for PDAC patients.

Their discoveries will help predict which patients are likely or not likely to benefit from traditional chemotherapy. The likely “responder” patients can be confidently treated with traditional chemotherapy regimens, while the likely “non-responder” patients can be given an alternate regimen–potentially a combination of epigenetic therapy. The technology addresses a pressing clinical need by introducing the first ever epigenetic precision medicine approach to pancreatic cancer, as a means toward better outcomes and quality of life for all patients.

Epigenetic therapy can reactivate expression of the regulatory genes that have been silenced in chemo-resistant tumors and therefore make the tumors responsive to chemotherapy.

The team’s work, entitled “Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility,” is newly published in Nature Communications.

“We have a discovery and an invention emanating from this work,” says Dhara. “By investigating all epigenetic elements that regulate genes in PDAC, we discovered that only about 1,092 elements are associated with chemotherapy resistance and early recurrence of this disease. Of those, 723 elements are silenced in chemo-resistant tumors, and are optimally predictive.”

To translate this knowledge into the clinic, Leach and Dhara invented a novel technology platform called “ATAC-array” that assesses gene regulatory elements as a means to predict chemotherapy response and the potential benefit of epigenetic therapy in patients with PDAC. The technology is DNA-based and can potentially be performed on fine-needle aspiration specimens collected from tumors at the time of diagnosis.

Although there are nine FDA-approved epigenetic drugs, and more in the pharma pipeline, a fundamental means of distinguishing tumors that would benefit from epigenetic reprogramming therapy is still lacking. “We currently appear to be at the dawn of a new era in which epigenetic reprogramming is poised to become increasingly relied upon to optimize therapeutic effectiveness in multiple tumor types,” says Leach. “With this work, we have pioneered a precision epigenetic approach in PDAC, a treatment approach that is now ready to be translated into the clinic.”

Leach and Dhara have co-founded Episteme Prognostics, Inc.– a precision medicine company developing therapeutic biomarkers for pancreatic cancer–in order to translate this work directly to the clinic as rapidly as possible.

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Senior corresponding author, Steven D. Leach, MD, is the director of Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC), Member of the NCCC Cancer Biology and Therapeutics Research Program, the Preston T. and Virginia R. Kelsey Distinguished Chair in Cancer, and Professor of Molecular and Systems Biology and of Surgery at the Geisel School of Medicine at Dartmouth. Dr. Leach’s laboratory has a long track record of research productivity in the field of pancreatic cancer biology and is known for establishing important links between pancreatic development and pancreatic cancer using both mouse and zebrafish model systems.

Co-Lead author, Surajit Dhara, PhD, is Senior Research Scientist at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC). Before joining NCCC, he led strategy development in clinical biomarker discovery at Memorial Sloan Kettering Cancer Center (MSK), bringing expertise in clinical biomarker discovery and precision oncology to NCCC. Dr. Dhara is lead inventor of the ATAC-array technology.

About Norris Cotton Cancer Center

Norris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth College’s Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT. NCCC is one of only 51 centers nationwide to earn the National Cancer Institute’s prestigious “Comprehensive Cancer Center” designation, the result of an outstanding collaboration between DHMC, New Hampshire’s only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.

About Dartmouth-Hitchcock Health

Dartmouth-Hitchcock Health (D-HH), New Hampshire’s only academic health system and the state’s largest private employer, serves a population of 1.9 million across northern New England. D-H provides access to more than 2,000 providers in almost every area of medicine, delivering care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was named again in 2020 as the #1 hospital in New Hampshire by U.S. News & World Report, and recognized for high performance in 9 clinical specialties and procedures. Dartmouth-Hitchcock also includes the Norris Cotton Cancer Center, one of only 51 NCI-designated Comprehensive Cancer Centers in the nation; the Children’s Hospital at Dartmouth-Hitchcock, the state’s only children’s hospital; affiliated member hospitals in Lebanon, Keene, and New London, NH, and Windsor, VT, and Visiting Nurse and Hospice for Vermont and New Hampshire; and 24 Dartmouth-Hitchcock clinics that provide ambulatory services across New Hampshire and Vermont. The D-H system trains nearly 400 residents and fellows annually, and performs world-class research, in partnership with the Geisel School of Medicine at Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.