Experimental therapy eliminates pancreatic precancerous cells in mice study

A new preclinical study in mice shows that precancerous cells in the pancreas can be eliminated before they have the chance to become tumors. Using an experimental therapy to target microscopic precancerous lesions in the pancreas nearly doubled survival in mouse models of pancreatic ductal adenocarcinoma (PDAC) compared to the same treatment given after cancer developed. The research, published today in Science, was led by physician-scientists in the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine's Abramson Cancer Center. It's the first time scientists have shown that a medical intervention could stop growth of pre-cancerous lesions in the pancreas before they develop into pancreatic cancer, providing strong evidence for the burgeoning field 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 on their earliest steps toward malignancy-it would be a game-changer."

Cancer interception is a distinct strategy from cancer prevention

Unlike prevention strategies-such as getting the HPV vaccine or stopping a smoking habit -which aim to prevent cancer from forming at all, cancer interception targets the earliest phases of a cell's path toward malignancy. Colonoscopy is an example of "mechanical" interception, as precancerous polyps are removed before they become colorectal cancer. Because cancer becomes more difficult to treat as it grows, the concept of treating premalignant growths before they become cancer is logical in theory, but difficult to prove. 

"This study provides a preclinical proof-of-concept that medical cancer interception works better than treatment after a diagnosis," said lead author Minh Than, MD, PhD, a clinical and research fellow in Hematology-Oncology. "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."

Cancer interception via RAS inhibition is effective in mice

For this study, the research team used two experimental inhibitors that target the cancer-causing gene, KRAS. More than 90 percent of pancreatic cancers are driven by KRAS mutations, the most common cancer-causing gene mutation across all cancer types, which was long considered "undruggable." In 2021, the first KRAS inhibitor was approved to treat non-small cell lung cancer, and since then, other KRAS inhibitors have moved into clinical trials for multiple cancer types, including pancreatic cancer.

Most PDAC tumors arise from microscopic lesions known as PanINs (pancreatic intraepithelial neoplasias) that are too small to see on scans, and almost all PanINs carry KRAS mutations. PanINs are common in adult pancreases, but only a very rare minority turn into cancer; scientists don't fully understand what causes this rare malignant switch. While this study was not focused on understanding the biology or improving detection of PanINs, the research team hypothesized that getting rid of these early lesions with KRAS inhibitors-even without knowing which ones have malignant potential-could be an effective strategy to prevent them from ever becoming PDAC.

The team assessed two compounds discovered by Revolution Medicines, whose scientists contributed to the study. Both compounds are designed to inhibit RAS when it is in an active or ON state and driving cancer growth. RMC-9945 is a preclinical tool compound that selectively targets KRAS G12D, the most common form of KRAS mutation in pancreatic cancer, and represents a class of oral RAS(ON) G12D-selective inhibitors, including the investigational drug candidate zoldonrasib (RMC-9805). RMC-7977 is a preclinical tool compound that targets multiple RAS(ON) variants and represents a class of oral RAS(ON) multi-selective inhibitors that includes the investigational drug candidate daraxonrasib (RMC-6236).

The research team used a Penn-developed immunocompetent mouse model with a healthy and functional immune system, considered the gold standard worldwide for preclinically assessing potential therapies for PDAC. First, they established a base timeline of PanIN to PDAC development in a control group. Then, they treated an intervention group with either RMC-9945 or RMC-7977, after PanIN development, but before tumor development. A reduction in the precancerous lesions was observed after 10 days of treatment, with an even more pronounced reduction after 28 days of treatment. At this milestone, tumors were slower to develop, and the survival of mice increased compared to mice that did not receive the intervention. The team then found that long-term treatment with RMC-7977 in PanIN-bearing mice tripled median overall survival time compared to the untreated control group with PanINs. Finally, the intervention group that received treatment before they developed tumors survived nearly twice as long as the group of mice that were only treated after tumor development.

Future clinical trial to focus on 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 aims to translate the research into a clinical trial focused on high-risk patients who are already being monitored for pancreatic cysts, larger growths than PanINs, that still have a low risk for cancer but are typically surgically removed if they grow to a certain size. If this approach were to move forward, the research team anticipates that it would be most applicable for individuals with a genetic predisposition for pancreatic cancer, including BRCA1, BRCA2, or PALB2 gene mutations, hereditary pancreatitis, precancerous cysts, or other strong risk factors. Eventually, the strategy could be considered for a broader range of individuals at intermediate risk.