Scientists Stop Pancreatic Cancer Before It Starts in Landmark Preclinical Study
Researchers have demonstrated a promising new approach to stopping pancreatic cancer before it starts, using experimental drugs to eliminate microscopic precancerous lesions in the pancreas.A new preclinical study in mice suggests that precancerous pancreatic cells can be removed before they progress into tumors.An experimental treatment aimed at microscopic precancerous lesions in the pancreas nearly doubled survival in mouse models of pancreatic ductal adenocarcinoma (PDAC) compared with giving the same therapy only after cancer appeared.
The research, published in Science, was led by physician scientists at the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center.It is the first demonstration that a medical treatment can halt the growth of precancerous pancreatic lesions before they become pancreatic cancer, offering strong support for the emerging 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 differs from prevention approaches such as HPV vaccination or quitting smoking, which are designed to stop cancer from forming in the first place.Instead, interception focuses on the earliest stages of a cell’s movement toward cancer.Colonoscopy is one example of physical interception, because doctors remove precancerous polyps before they can develop into colorectal cancer.Since cancer generally becomes harder to treat as it advances, treating premalignant growths before they turn cancerous makes sense in principle, though it has been 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.”
In this study, researchers tested two experimental drugs that target KRAS, a gene responsible for more than 90 percent of pancreatic cancers.KRAS is the most commonly mutated cancer related gene and was once considered impossible to target with drugs.The first KRAS inhibitor was approved for non-small cell lung cancer in 2021, and several others are now being tested in clinical trials, including for pancreatic cancer.
Most pancreatic ductal adenocarcinoma (PDAC) tumors begin as tiny precancerous lesions called PanINs (pancreatic intraepithelial neoplasias), which are too small to detect on scans.Nearly all PanINs carry KRAS mutations. Although these lesions are common, only a small fraction become cancerous.The researchers proposed that eliminating PanINs with KRAS inhibitors could prevent them from developing into PDAC.
The team studied two compounds developed by Revolution Medicines. RMC-9945 (Synonyms: RM-044) selectively targets KRAS G12D, the most common KRAS mutation in pancreatic cancer, and represents a class of inhibitors that includes the investigational drug zoldonrasib (RMC-9805).RMC-7977 targets multiple RAS(ON) variants and represents a class that includes the investigational drug daraxonrasib (RMC-6236).
Using a widely accepted mouse model of PDAC with fully functioning immune systems, the researchers treated animals after PanINs had formed but before tumors appeared.After 10 days, the number of precancerous lesions had fallen, with larger reductions after 28 days.Tumor growth slowed, and treated mice lived longer than untreated mice.Long-term treatment with RMC-7977 tripled median overall survival, while mice treated before tumors formed lived nearly twice as long as those treated only after tumors developed.
