A preclinical study published on Mar. 12 shows that an experimental therapy can eliminate precancerous cells in the pancreas of mice before they develop into tumors. The research, led by physician-scientists at the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine's Abramson Cancer Center, found that targeting microscopic precancerous lesions nearly doubled survival rates in mouse models of pancreatic ductal adenocarcinoma compared to treatment after cancer had developed.
This finding is significant because pancreatic cancer has limited treatment options and a poor prognosis. The study provides evidence for the concept of cancer interception—intervening during the earliest stages of abnormal cell development to prevent malignancy. "I'm convinced that cancer interception will become the next frontier of cancer therapy," said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center. "Pancreatic cancer has a stubbornly poor prognosis, limited treatment options and no proven screening or prevention strategies. If we can find a way to intercept it—to identify and neutralize abnormalities on their earliest steps toward malignancy—it would be a game-changer."
Unlike traditional prevention methods such as vaccines or lifestyle changes, cancer interception targets early cellular changes before they progress to full-blown cancer. Colonoscopy is cited as an example where precancerous polyps are removed before becoming colorectal cancer. However, proving this approach works for other cancers has been challenging.
Lead author Minh Than, MD, PhD, said: "This study provides a preclinical proof-of-concept that medical cancer interception works better than treatment after a diagnosis. This study shows us the power of being proactive, rather than reactive, when it comes to cancer. It will be exciting to evaluate this in our patients in the next phase of this work." The team used two experimental inhibitors targeting KRAS mutations—a gene implicated in over 90 percent of pancreatic cancers—which were previously considered difficult to target with drugs.
The compounds tested were RMC-9945 and RMC-7977 from Revolution Medicines; both are designed to inhibit active forms of RAS proteins driving tumor growth. Using a specialized mouse model with an intact immune system, researchers observed that treating mice with these inhibitors after PanIN (pancreatic intraepithelial neoplasia) development but before tumor formation reduced lesion numbers and slowed tumor progression. Long-term treatment tripled median survival time compared to untreated controls.
Ben Stanger, MD, PhD, co-corresponding author and director of the Penn Pancreatic Cancer Research Center said: "The direct comparison in this study puts PanINs on the map as potential targets for cancer interception and opens the door for exploring KRAS inhibitors in a new setting. However, because PanINs cannot be seen on imaging exams...we have to think carefully about how to apply this preclinical research to the right population for human studies." The team plans future clinical trials focusing on high-risk individuals already monitored for pancreatic cysts or those with genetic predispositions.
