Predicting chemotherapy response and tailoring treatments for pancreatic cancer patients

STATUE: (LR) Dartmouth and Dartmouth-Hitchcock’s Norris Cotton Cancer Center Director Steven D. Leach, MD, and Surajit Dhara, PhD, Senior Research Scientist in the Leach Laboratory are about to change … view more

Credit: Mark Washburn

LEBANON, NH – By 2030, pancreatic ductal adenocarcinoma (PDAC), the most deadly form of pancreatic cancer, is expected to become the second leading cause of cancer-related deaths in the United States. Not only are the therapeutic options limited, but nearly half of all PDAC patients whose tumors have been surgically removed will experience relapse of the disease within a year, despite receiving additional chemotherapy. For more advanced stages, only about a 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 from 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 “responding” patients can be confidently treated with traditional chemotherapy regimens, while the likely “unresponsive” patients can receive an alternative regimen – possibly a combination of epigenetic therapy. The technology addresses an urgent clinical need by introducing the first-ever precision epigenetic medicine approach to pancreatic cancer as a means to better outcomes and quality of life for all patients.

Epigenetic therapy can reactivate the expression of the regulatory genes silenced in chemo-resistant tumors and thereby render the tumors responsive to chemotherapy.

The team’s work, entitled “Pancreatic Cancer Prognosis Predicted by an ATAC Array Technology for Assessing Chromatin Accessibility,” was recently published in Nature Communications.

“We have a discovery and an invention that comes out of this work,” says Dhara. “By examining all epigenetic elements that regulate genes in PDAC, we found that only about 1,092 elements are associated with chemotherapy resistance and early recurrence of this disease. Of these, 723 elements are silenced in chemoresistant tumors, and are optimally predictive. “

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

While there are nine FDA-approved epigenetic drugs, and more in the pharmaceutical pipeline, there is no fundamental means of distinguishing tumors that would benefit from epigenetic reprogramming therapy. “We currently appear to be at the dawn of a new era in which epigenetic reprogramming is on the verge of becoming increasingly familiar with optimizing therapeutic effectiveness in multiple tumor types,” says Leach. “With this work, we have pioneered an epigenetic precision approach to PDAC, a treatment approach now ready to be translated into the clinic.”

Leach and Dhara have partnered up Episteme Prognostics, Inc. founded a precision medicine company developing therapeutic biomarkers for pancreatic cancer, to translate this work directly to the clinic as soon as possible.

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Senior corresponding author, Steven D. Leach, MD, is the director of the Norris Cotton Cancer Center (NCCC) of Dartmouth and Dartmouth-Hitchcock, 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 Surgery at the Geisel School of Medicine, Dartmouth. Dr. Leach has a long track record of research productivity in pancreatic cancer biology and is known for making important links between pancreatic development and pancreatic cancer using both mouse and zebrafish model systems.

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

About Norris Cotton Cancer Center

Located on the Dartmouth-Hitchcock Medical Center (DHMC) campus in Lebanon, NH, Norris Cotton Cancer Center combines advanced cancer research at Dartmouth College’s Geisel School of Medicine in Hanover, NH with the highest levels of high quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as regional, multidisciplinary locations and partner hospitals in NH and VT. NCCC is one of only 51 centers nationwide to be awarded the National Cancer Institute’s prestigious “Comprehensive Cancer Center” title, the result of an excellent partnership between DHMC, New Hampshire’s only academic medical center, and Dartmouth College . As the fifth decade enters, NCCC remains committed to excellence, outreach and education, striving to prevent and cure cancer, improve survival and promote cancer health equality through cutting-edge interdisciplinary research. Each year, the NCCC schedules 61,000 appointments with 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 people in northern New England. DH provides access to more than 2,000 health care providers in nearly every field of medicine and delivers care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was again named as the # 1 hospital in New Hampshire by US News & World Report in 2020, 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 country; the Children’s Hospital at Dartmouth-Hitchcock, the state’s only children’s hospital; affiliated 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 providing outpatient services in New Hampshire and Vermont. The DH system annually trains nearly 400 residents and fellows and conducts world-class research in partnership with the Geisel School of Medicine in Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.

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