Pancreatic Cancer Interception: Novel Research Offers Hope for Early Treatment

PHILADELPHIA – A new preclinical study in mice suggests that eliminating precancerous cells in the pancreas before they develop into tumors could significantly improve survival rates. Researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center found that targeting microscopic precancerous lesions with an experimental therapy nearly doubled survival in mouse models of pancreatic ductal adenocarcinoma (PDAC) compared to the same treatment administered after cancer developed. The research, published in Science, marks the first demonstration that a medical intervention can halt the growth of precancerous pancreatic lesions before they evolve into pancreatic cancer, bolstering the emerging field of cancer interception.

The Promise of Cancer Interception

“I’m convinced that cancer interception will become the next frontier of cancer therapy,” said co-corresponding author 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 at their earliest steps toward malignancy—it would be a game-changer.”

Cancer interception differs from traditional cancer prevention. While prevention strategies, such as vaccination or lifestyle changes, aim to prevent cancer from forming altogether, interception targets the earliest stages of a cell’s progression toward malignancy. A colonoscopy, where precancerous polyps are removed before becoming colorectal cancer, serves as an example of “mechanical” interception.

Study Details: Targeting KRAS Mutations

The study focused on inhibiting the KRAS gene, which is mutated in over 90% of pancreatic cancers and, historically, considered “undruggable.” Recent advancements have led to the development of KRAS inhibitors, with the first approved for non-small cell lung cancer in 2021 and others undergoing clinical trials for various cancers, including pancreatic cancer.

PDAC often originates from microscopic lesions called PanINs (pancreatic intraepithelial neoplasias), which commonly appear in adult pancreases but rarely transform into cancer. The research team hypothesized that eliminating these early lesions with KRAS inhibitors, even without identifying those with malignant potential, could effectively prevent PDAC development.

Researchers assessed two compounds developed by Revolution Medicines: RMC-9945, which selectively targets KRAS G12D, the most common KRAS mutation in pancreatic cancer, and RMC-7977, which targets multiple RAS(ON) variants. Using a Penn-developed mouse model with a functional immune system, the team observed a reduction in precancerous lesions after 10 days of treatment, with a more significant reduction after 28 days. Tumor development was slower, and survival rates increased in treated mice compared to controls.

Long-term treatment with RMC-7977 in PanIN-bearing mice tripled median overall survival time compared to untreated controls. Mice treated before tumor development survived nearly twice as long as those treated after tumors appeared.

Future Directions: Clinical Trials for High-Risk Patients

“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,” said co-corresponding author Ben Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center. “However, because PanINs cannot be seen on imaging exams, and we are talking about treating individuals who do not have a cancer diagnosis, we have to think carefully about how to apply this preclinical research to the right population for human studies.”

The team plans to translate this research into a clinical trial focusing on high-risk patients already monitored for pancreatic cysts—growths larger than PanINs with a low cancer risk but often surgically removed if they grow. This approach may be particularly applicable to individuals with a genetic predisposition to pancreatic cancer, such as those with BRCA1, BRCA2, or PALB2 gene mutations, hereditary pancreatitis, or other significant risk factors. Eventually, the strategy could be considered for a broader range of individuals at intermediate risk.

Patients interested in joining a pancreatic cancer clinical trial at Penn Medicine can learn more here.

Funding

The research was funded by the National Institutes of Health (R01CA276512, R01CA252225, T32 CA009615), Department of Defense (W81XWH2210730), Conquer Cancer, Penn Medicine’s Basser Center for BRCA, and Revolution Medicines, along with philanthropic support.