A rare genetic mutation discovered by a researcher at Brigham and Women’s Hospital could hold the clues to developing new management strategies for pancreatic cancer. Sahar Nissim, MD, PhD, assistant professor of medicine in the Brigham’s Gastroenterology, Hepatology and Endoscopy & Genetics Divisions, found the mutation in a single family with a strong history of pancreatic cancer and published his findings in Nature Genetics. He said the discovery may have broader implications for all patients with pancreatic cancer, regardless of whether or not they have the mutation.
“About 10 percent of pancreatic cancer cases are familial,” Dr. Nissim explained. “The hereditary basis for most of these families is not known. While rare, identifying the causal genetic mutation can give us precious insights into how pancreatic cancer occurs.”
Dr. Nissim said that although a few of the pancreatic cancer families have mutations in known genes such as BRCA-1 and BRCA-2 genes, the genetic explanation has not been identified in most families. His study uncovered a new mutation in the gene known as RABL3, which accelerates the movement of a pancreatic cancer protein, KRAS. His research group is now investigating whether targeting RABL3 could disrupt the trafficking of KRAS to the cell’s plasma membrane, thereby interfering with the ability of KRAS to drive cancer development.
Encouraging Translational Potential
According to Dr. Nissim, the discovery gives clinicians a new genetic etiology to test for, which will help to guide risk assessment, surveillance and potential new treatments.
“The Brigham has longitudinally followed families with a strong history of pancreatic cancer but no genetic explanation for that cancer,” he said. “One of our goals is to work with commercial comprehensive genetic testing programs to add this gene onto their germline panels so we can identify those at higher risk.”
“Pinpointing patients at high risk of some hereditary cancers allows surgeons to prophylactically remove the organ involved at a relatively low risk of morbidity compared with the risks associated with the cancer developing further,” said Stanley W. Ashley, MD, professor of surgery in the Brigham’s Division of General and Gastrointestinal Surgery. “Unfortunately, most pancreatic cancer is identified at an advanced stage, and while surgery is the only option for a cure, we can’t remove the pancreas prophylactically due to the high morbidity of the surgery.
“This discovery gives us the tools we need to catch cancer earlier, when more treatment options are available.”
A Paradigm Shift in Pancreatic Cancer Treatment
Typically, individuals with a high risk of pancreatic cancer are enrolled in a surveillance program with annual magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasounds. This “watch and wait” approach can extend for many years, and the hope is that surveillance may allow better outcomes if a cancer is detected earlier.
However, there are no medical options to offer these individuals that can prevent the cancer from forming. Dr. Nissim’s research group is seeking to pioneer a so-called “interception” strategy that can actively target a cancer in the earliest stages, long before it becomes intractable.
Dr. Nissim said that while a number of genome-wide association studies have uncovered various pathways that modulate the risk of pancreatic cancer, nobody has tried to pharmacologically target these pathways to reduce the risk of pancreatic cancer or keep it from forming. Studies have shown that the time between an initiating mutation and development of invasive cancer is over a decade.
“We have a tremendous untapped window of opportunity for interception,” he said. “Our strategy focuses on the signaling and epigenetic changes in pancreas cells that occur following an initiating KRAS mutation. By pharmacologically bolstering the pathways that maintain normal cell identity, we hope to prevent the cell from progressing to an invasive cancer. Our ultimate goal is development of a medication people can take daily, similar to taking a daily low-dose aspirin or statin to prevent heart attacks and strokes. This would be a paradigm shift in our battle against pancreatic cancer.”
Detecting New Biomarkers for Pancreatic Cancer
Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) sees a high volume of pancreatic cancer patients and high-risk individuals. Dr. Nissim said this allows clinicians and researchers to prospectively monitor those with a strong family history of the disease. DF/BWCC is collecting imaging studies and pancreatic juice samples from these individuals and applying unbiased approaches, including artificial intelligence and machine learning, to detect new biomarkers that might identify pancreatic cancer even before it can be detected by MRCP or endoscopic ultrasounds.
“Less than a third of pancreatic cancer patients are candidates for surgery,” concluded Dr. Ashley. “They present at such a late stage that the only option for them is palliative chemotherapy. We think we can make a bigger impact and improve outcomes by learning how to intervene at an early enough stage for curative resection.”