Targeting cancer cells big appetite for glutamine with a 'prodrug'

The researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Scientists have dubbed this type of targeted approach a “prodrug” — a medicine designed to release its payload in a particular area of the body and in no other areas. The Johns Hopkins-discovered prodrug, called DRP-104 (sirpiglenastat), is in early-stage clinical trials in people with advanced solid tumors. The newly published studies in mice show that the augmented drug preferentially eliminates cancer cells but does not harm healthy cells.

A report of their experiments is published in Science Advances.

“Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach. What is unique about our approach is that we utilized a novel chemistry design to create a prodrug that was simultaneously bio-activated in cancer cells but bio-inactivated in healthy tissues such as the gut. This preferential targeting of the payload to cancer cells is now enabling this efficacious class of drugs to be reevaluated safely in people,” says the study author.

The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called “glutamine addiction,” but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine.

A co-author says, “DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut.” 

Development of this promising class of drugs did not resume until the team decided to make chemical modifications to DON. 

"We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut,” says the author. “This specific prodrug design made DON targeted to its intended destination (tumor) and have less of an impact on healthy cells elsewhere.”

For the new study, researchers gave the original DON drug and the souped-up DRP-104 drug to mice implanted with tumors. In mice that received DRP-104, the researchers found 11 times more active drug in the tumor compared with the gastrointestinal tract (gut). Both drugs completely wiped out the tumor, but DON caused more gut toxicity in the mice than DRP-104.