BY EBELE ORAKPO with Agency report

Scientists at the Massachusetts Institute of Technology (MIT), Dana-Farber Cancer Institute and the Broad Institute have discovered that people suffering from pancreatic cancer have very high levels of certain amino acids in their bloodstream  years before they show any other signs of the disease.

This is good news as it will increase survival rate in a disease that has very low survival rate. This finding, they believe, could offer new insights into developing early diagnostics for pancreatic cancer.

“Most people with pancreatic ductal adenocarcinoma (PDAC) (most common form of pancreatic cancer, are diagnosed after the disease has reached an advanced stage, and many die within a year of diagnosis,” said Brian Wolpin, assistant professor of medical oncology at Dana-Farber and a clinical epidemiologist, co-senior author of the study with Matthew Vander Heiden, associate professor of Biology, and member of MIT’s Koch Institute for Integrative Cancer Research.

“Detecting the disease earlier in its development may improve our ability to treat it successfully. In this study, we asked whether PDAC produces metabolic changes – changes in the way the body uses energy and nutrients – that can be detected before the disease is diagnosed.”

The process: The researchers analysed blood samples from 1,500  participants. They then compared samples from people who were eventually diagnosed with pancreatic cancer and samples from those who were not.

Nature medicine
The findings of the study published in Nature Medicine, were described as ‘dramatic.’ They noticed that people with a surge in amino acids known as branched chain amino acids (BCAAs) such as  leucine, isoleucine and valine, were far more likely to be diagnosed with pancreatic cancer within one to 10 years.

“Pancreatic cancer, even at its very earliest stages, causes breakdown of body protein and deregulated metabolism. What that means for the tumor, and for the health of the patient—are long-term questions still to be answered,” says Vander Heiden.

Wolpin on his part, assembled the patient sample from several large public-health studies. All the patients had their blood drawn at the beginning of the study and subsequently filled out annual health questionnaires.

Analysis:
The researchers analyzed blood samples for more than 100 different metabolites— proteins and sugars, produced as by-products of metabolic processes.

“What we found was that this really interesting signature fell out as predicting pancreatic cancer diagnosis, which was elevation in these three branched chain amino acids: leucine, isoleucine and valine,” Vander Heiden says. These three BCAAs are among the 20 amino acids which are the building blocks for proteins normally found in the human body.

Interestingly, the study reported that some of the patients in the study were diagnosed with pancreatic cancer one year after their blood samples were taken, while others were diagnosed two, five or even 10 years later.

“We found that higher levels of BCAAs were present in people who went on to develop pancreatic cancer compared to those who did not develop the disease,” Wolpin says.

Hypothesis:
“These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor,” stated Wolpin.

Early protein breakdown
This hypothesis was tested by Vander Heiden’s laboratory. They studied mice genetically programmed to develop pancreatic cancer. “Using those mouse models, we found that we could perfectly recapitulate these exact metabolic changes during the earliest stages of cancer,” Vander Heiden says, adding: “What happens is, as people or mice develop pancreatic cancer, at the very earliest stages, it causes the body to enter this altered metabolic state where it starts breaking down protein in distant tissues.

“The findings may also allow scientists to pursue new treatments that would work by targeting tumor metabolism and cutting off a tumor’s nutrient supply.”

David Tuveson,  professor at the Cancer Center, Cold Spring Harbor Laboratory who was not involved in the work has this to say: “This is a finding of fundamental importance in the biology of pancreatic cancer. It really opens a window of possibility for labs to try to determine the mechanism of this metabolic breakdown.”

Early protein breakdown and cachexia:
The researchers are now investigating why this protein breakdown, which has not been seen in other types of cancer; why it occurs in the early stages of pancreatic cancer. They suspect that pancreatic tumors may be trying to feed their own appetite for amino acids that they need to build cancerous cells. They are also “exploring possible links between this early protein breakdown and the wasting disease known as cachexia, which often occurs in the late stages of pancreatic cancer,” says the report.

Also to be answered is the question of whether this signature could be used for early detection. The findings need to be validated with more data, and it may be difficult to develop a reliable diagnostic based on this signature alone, Vander Heiden says. However, he believes that studying this metabolic dysfunction further may reveal additional markers such as misregulated hormones that could be combined to generate a more accurate test.