Predicting chemotherapy response and tailoring remedies for pancreatic most cancers sufferers

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PICTURE: (LR) Steven D. Leach, MD, Dartmouth and Dartmouth-Hitchcocks Director of the Norris Cotton Cancer Center, and Surajit Dhara, PhD, Senior Research Scientist in the Leach Laboratory, are in the process of making changes in the … view More

Photo credit: Mark Washburn

LEBANON, NH – By 2030, ductal pancreatic adenocarcinoma (PDAC), the deadliest form of pancreatic cancer, is projected to be the second leading cause of cancer-related death in the United States. The therapeutic options are not only limited; almost half of all PDAC patients whose tumors have been surgically removed suffer a relapse within a year despite additional chemotherapy. At more advanced stages, only about a third of patients have a limited response to approved chemotherapy.

A team of researchers led by Steven D. Leach, MD, Director of the Norris Cotton Cancer Center (NCCC) in Dartmouth and Dartmouth-Hitchcock, and Dr. Surajit Dhara, Senior Research Scientist at 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.

Your discoveries will help predict which patients are likely to benefit or not from traditional chemotherapy. The likely “responder” patients can be safely treated with conventional chemotherapy regimens, while the likely “non-responder” patients can receive alternative treatment – possibly a combination of epigenetic therapy. The technology addresses an urgent clinical need by introducing the very first epigenetic precision medicine approach in pancreatic cancer to deliver better outcomes and quality of life for all patients.

Epigenetic therapy can reactivate the expression of the regulatory genes that have been silenced in chemoresistant tumors and therefore the tumors respond to chemotherapy.

The team’s work, “Pancreatic Cancer Prognosis Predicted by ATAC Array Technology to Assess Chromatin Accessibility,” is newly published in Nature Communications.

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

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

Although there are nine FDA-cleared epigenetic drugs and more in the pharmaceutical pipeline, there is still a lack of a basic means of differentiating between tumors that would benefit from epigenetic reprogramming therapy. “We seem to be at the dawn of a new era in which epigenetic reprogramming is increasingly being used to optimize therapeutic efficacy on multiple tumor types,” says Leach. “With this work, we pioneered a precision epigenetic approach in PDAC, a treatment approach that is now ready to be carried over to the clinic.”

Leach and Dhara co-founded Episteme Prognostics, Inc., a precision medicine company developing therapeutic biomarkers for pancreatic cancer, to bring that work straight 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, 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 the pancreatic cancer biology and is known for making important links between pancreatic development and pancreatic cancer using mouse and zebrafish model systems.

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

About the Norris Cotton Cancer Center

The Norris Cotton Cancer Center on the Dartmouth-Hitchcock Medical Center (DHMC) campus in Lebanon, NH, combines advanced cancer research at the Geisel School of Medicine at Dartmouth College in Hanover, NH with the ultimate in quality, innovative and personalized and compassionate patient-centered cancer care at the DHMC as well as at regional, multidisciplinary locations and partner hospitals throughout NH and VT. The NCCC is one of only 51 centers nationwide to have received the National Cancer Institute’s prestigious Comprehensive Cancer Center award, the result of an excellent collaboration between the DHMC, New Hampshire’s only academic medical center, and Dartmouth College . Now entering its fifth decade, the NCCC continues to advocate excellence, outreach and education, striving to prevent and cure cancer, improve survival, and promote cancer equity through its groundbreaking interdisciplinary research. Each year, the NCCC plans 61,000 appointments for nearly 4,000 newly diagnosed patients and currently offers more than 100 active clinical trials to its patients.

Via Dartmouth-Hitchcock Health

Dartmouth-Hitchcock Health (D-HH), New Hampshire’s only academic health care system and the state’s largest private employer, serves 1.9 million residents in northern New England. DH provides access to more than 2,000 providers in almost all areas of medicine and cares for them at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was re-named New Hampshire’s No. 1 Hospital in 2020 by the US 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 Dartmouth-Hitchcock Children’s Hospital, the only children’s hospital in the state; 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 offering outpatient services in New Hampshire and Vermont. The DH system trains nearly 400 residents and fellows annually, 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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