Princess Margaret Cancer Centre scientists have identified a specific genetic alteration which drives a very aggressive subtype of pancreatic cancer, paving the way for the development of more precise, targeted treatments in the future.
A team of international researchers, led by Princess Margaret Cancer Centre and Ontario Institute for Cancer Research (OICR) scientist Dr. Faiyaz Notta, and surgical oncologist Dr. Steven Gallinger, sought to explain why patients respond differently to the same chemotherapies in pancreatic cancer: "Could there be specific genes or genomic features that are linked to these responses?"
Scientists found there are five molecular subtypes (Basal-like-A, Basal-like-B, Hybrids, Classical-A and Classical-B) of pancreatic cancer. One of these molecular subtypes, Basal-like-A, was highly enriched in patients with metastatic disease, and patients with these tumours had the worst prognosis.
They also found that KRAS, a gene mutated in 90 per cent of pancreatic cancer, was amplified in many of the Basal-like-A tumours. Amplification means that there were multiple DNA copies of the mutant KRAS rather than just one copy which is found in most tumours.
The team of scientists published their results in Nature Genetics, Jan. 13, in an article titled, "Transcription Phenotypes of Pancreatic Cancer are Driven by Genomic Events During Tumor Evolution."
Identified as one of the first oncogenes about 30 years ago, KRAS is being actively researched around the world for potential personalized therapies, since KRAS-driven cancers are currently difficult to treat.
Sometimes called "undruggable," efforts to develop medications to target this genetic mutation have not been highly successful in most cases. A drug for a rare form of the KRAS mutation (known as G12C) has been developed, but this type of KRAS mutation is very rare in pancreatic cancer.
The study involved tumours with both local and metastatic pancreatic disease, which are very difficult to obtain for research. However, the one-of-a-kind clinical trial at Princess Margaret known as COMPASS, which focuses on deep molecular characterization of patients with advanced disease, made this study feasible. Dr. Jennifer Knox is the Principal Investigator of the COMPASS trial at the Princess Margaret.
Fourth leading cause of cancer-related death in Canada
The study, which examined a wide spectrum of 248 human pancreatic cancer tumours, is the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date.
"These Basal-like-A tumours are, so far, resistant to anything you throw at them," explains Dr. Notta, who is also an Assistant Professor, Medical Biophysics, University of Toronto (U of T). “Nothing seems to touch them.
"The finding that mutant KRAS may be the underlying resistance mechanism will allow us to study how to overcome this resistance. We hope to develop new targets against this specific subtype."
As technology improves, we’re seeing things that we didn't expect to see with in-depth sequencing of tumours, says Dr. Gallinger, who is also Professor of Surgery, U of T.
"We can identify the molecular subtypes that are only present in advanced disease that we did not see before," he says. "We can now start thinking about what’s the best therapy for your disease subtype."
An estimated 5,800 Canadians will be diagnosed with pancreatic cancer in one year, and 5,200 Canadians will die from pancreatic cancer.
It is the fourth leading cause of cancer-related death in Canada and has recently surpassed breast cancer to become the third leading cause of cancer death in the United States. The biological basis of its aggressive nature and role in treatment resistance is still not well understood.
Support for this study includes: Ontario Institute for Cancer Research, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Pancreatic Cancer Canada Foundation, Canadian Cancer Society, and the Canadian Friends of the Hebrew University.
Read more about the study
