Researchers find a new therapeutic target in pancreatic cancer

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A new study uncovers how the most commonly mutated tumor suppressor gene in cancer and the most commonly mutated oncogene in cancer cooperate to drive formation of pancreatic cancer

LEBANON, NH – The development of pancreatic cancer is driven by co-existing mutations in an oncogene involved in controlling cell growth, called KRAS, and in a tumor suppressor gene, called p53. But how these mutations cooperate to promote cancer is unknown. A new study co-led by Steven Leach, MD, Director of Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC), uncovers a direct link between these mutations and the mechanism that regulates cell activity, providing insight for future development of therapeutics that could hit this newly found target in pancreatic cancer.

The study is co-led by Leach; Omar Abel-Wahab, MD, Associate Member in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center (MSKCC); and Luisa Escobar-Hoyos, PhD, MSc, Assistant Professor of Therapeutic Radiology at Yale School of Medicine and former post-doc in the Leach laboratory at MSKCC. Dr. Escobar-Hoyos conceived of and performed the work and serves as lead author, while Dr. Leach serves as co-senior author and along with Dr. Abdel-Wahab supervised the work, both while at MSKCC and while at NCCC. “The most commonly mutated tumor suppressor gene in cancer, p53, dramatically rewires RNA splicing, the fundamental cell mechanism by which RNA is processed before being translated into protein. The rewiring is done in a manner that leads to further activation of the KRAS oncogene, the major ‘driver’ gene in human pancreatic cancer,” explains Leach.

The team analyzed every known mRNA splice variant encoded by the human genome – more than 200,000 possible sequences, in hundreds of pancreatic cancer patients. Their findings, “Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer” are newly published in Cancer Cell. “Our paper shows that a new class of drugs that alter RNA splicing have selective activity against p53-mutant pancreatic cancers,” says Leach.

This study shows that there are still fundamental mechanisms to be discovered in cancer that can lead to new treatment strategies. Based on these findings, next steps will be to design clinical trials that will evaluate these new drugs in patients with pancreatic cancer.

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Steven D. Leach, MD, is the Director of Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center, and Professor of Molecular and Systems Biology, Professor of Surgery, and Professor of Medicine at the Geisel School of Medicine at Dartmouth, as well as the Preston T. and Virginia R. Kelsey Distinguished Chair in Cancer. Research interests include establishing important links between pancreatic development and pancreatic cancer using both mouse and zebrafish model systems.

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.

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http://dx.doi.org/10.1016/j.ccell.2020.05.010

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