Scientists have been trying to stop cancer by starving tumor cells of nutrients. Now a team of researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) has offered fresh insights into how that might be done, pointing to a possible way of developing new drugs to treat pancreatic cancer.
Pancreatic tumor cells can turn to a nutrient supply route, called macropinocytosis, to survive and continue growing. Scientists hope to block this process, otherwise known as “cellular drinking,” to starve pancreatic tumors. But what molecular signaling pathway should they target?
Cosimo Commisso, Ph.D., and colleagues at SBP found that the “metabolic Achilles’ heel” of pancreatic cancer could be the amino acid glutamine. They described the discovery in the journal Developmental Cell.
The team analyzed cell lines from people with pancreatic ductal adenocarcinoma—the most common type of pancreatic cancer—and used a mouse model of human pancreatic cancer. They found that in some cell lines, removing glutamine increased macropinocytosis, while others didn’t respond to changes in glutamine levels. This could mean that glutamine depletion causes some pancreatic tumor cells to be more sensitive to drugs that target macropinocytosis, they suspected.
Specifically, in cells located inside tumors, the researchers observed elevated macropinocytosis. More importantly, they showed that two well-known cancer signaling pathways, EGFR and Pak, are the key molecular regulators of glutamine-sensitive macropinocytosis, according to a statement.
Some biotech companies are pursuing a strategy of blocking cancer metabolism pathways to starve tumor cells. French biotech Erytech Pharma, for example, is working on a drug called eryaspase, which encapsulates the enzyme L-asparaginase in red blood cells. L-asparaginase breaks down the amino acid asparagine, which is a key nutrient for cancer cells. The company recently received FDA clearance to begin a phase 3 trial for eryaspase in pancreatic cancer and just enrolled its first patient in a phase 2 trial testing the drug in triple-negative breast cancer.
Other academic researchers have been studying the role of glutamine in cancer. A team of researchers in France recently found that cutting off glutamine supply was enough to restore the ability of some cisplatin-resistant non-small cell lung cancer and ovarian cancer cell lines to respond to the chemotherapy.
And several teams are pursuing different cancer-metabolism pathways. Last year, researchers led by Duke University and the National University of Singapore reported that inhibiting sugar intake while simultaneously boosting calcium in cancer cells could kill rogue cancer cells. Previously, scientists at New York University’s School of Medicine found that pancreatic cancer cells use macropinocytosis to consume the protein albumin, which helps them maintain growth. By blocking albumin uptake in mice, the researchers stopped tumor growth and saw some tumors shrink.
SBP’s Commisso and his team plan to explore how pancreatic tumor cells sense glutamine levels. They believe that inhibiting that sensing mechanism could prevent the activation of macropinocytosis in pancreatic cancer, leading to tumor starvation.
The team also hopes their discovery of glutamine’s role in different cells and macropinocytosis’ molecular regulators could lead to personalized treatments for pancreatic cancer and more. “In addition to pancreatic cancer, macropinocytosis is prevalent in other cancer types, including lung, prostate, bladder and breast tumors,” Commisso said in the statement.
