Cancer Interception: New Approach Shows Promise in Pancreatic Cancer Models

A new preclinical study in mice demonstrates that eliminating precancerous cells in the pancreas before they develop into tumors is possible. The research, led by scientists at the University of Pennsylvania’s Perelman School of Medicine and the Abramson Cancer Center, shows that targeting microscopic precancerous lesions with an experimental therapy nearly doubled survival rates in mouse models of pancreatic ductal adenocarcinoma (PDAC) compared to treating the cancer after it had developed. Published in Science, the study provides the first evidence supporting a “cancer interception” strategy for pancreatic cancer.

The Promise of Cancer Interception

“I’m convinced that cancer interception will turn into the next frontier of cancer therapy,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center. Pancreatic cancer is notoriously difficult to treat, with a stubbornly poor prognosis and limited treatment options. The ability to identify and neutralize abnormalities at their earliest stages could be a game-changer.

Cancer interception differs from cancer prevention. While prevention strategies, like vaccination or lifestyle changes, aim to stop cancer from forming altogether, interception targets the earliest phases of a cell’s progression toward malignancy. A familiar example of interception is colonoscopy, where precancerous polyps are removed before they can become colorectal cancer.

Targeting KRAS Mutations

The study focused on KRAS mutations, which are present in over 90% of pancreatic cancers and in almost all pancreatic intraepithelial neoplasms (PanINs)—microscopic lesions that often precede cancer development. KRAS was long considered an “undruggable” target, but the recent approval of a KRAS inhibitor for non-small cell lung cancer in 2021 has opened new avenues for research.

Researchers tested two experimental inhibitors developed by Revolution Medicines: RMC-9945, which selectively targets the KRAS G12D mutation (the most common in pancreatic cancer), and RMC-7977, which targets multiple RAS variants. Both compounds inhibit RAS when it is in an active state, driving cancer growth.

Study Findings in Mouse Models

Using a specialized mouse model developed at the University of Pennsylvania with a functional immune system, the research team observed significant reductions in precancerous lesions after 10-28 days of treatment with either RMC-9945 or RMC-7977. Tumor development was slower, and survival rates increased compared to untreated mice. Long-term treatment with RMC-7977 tripled median overall survival time in mice with PanINs. Importantly, mice treated before developing tumors survived nearly twice as long as those treated only after tumor development.

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 Ben Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center.

The team plans to translate these findings into a clinical trial focusing on high-risk patients already monitored for pancreatic cysts or those with genetic predispositions to pancreatic cancer, such as mutations in the BRCA1, BRCA2, or PALB2 genes, or hereditary pancreatitis. This strategy could eventually be considered for a broader range of individuals at intermediate risk.

Understanding Pancreatic Cancer and the Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense and complex tumor microenvironment, including fibroblasts, blood vessels, and immune cells. This microenvironment contributes to the remarkable resistance of pancreatic cancer to treatment, including immunotherapy. The Beatty Laboratory at the University of Pennsylvania focuses on understanding these mechanisms of resistance and response to immunotherapy, particularly in PDAC.

In 2021, approximately 60,430 people in the United States were diagnosed with pancreatic cancer, and 48,220 died from the disease. The five-year survival rate remains at a dismal 10%, highlighting the urgent need for new and effective therapies.