Targets cancer cells' appetite for glutamine and keeps healthy cells from harm

Researchers at Johns Hopkins University School of Medicine have improved an anti-cancer drug that better targets cancer cells without harming healthy tissue
.
Scientists call this targeted approach "prodrug" — a drug designed to release payload in specific areas of the body, but not in other areas
.
The prodrug DRP-104 (sirpiglenastat), discovered by Johns Hopkins University, is currently in early clinical trials in patients with advanced solid
tumors.
Newly published mouse studies show that booster drugs preferentially eliminate cancer cells but do not harm healthy cells
.

Their experimental report was published Nov.
16 in Science Advances.

"Our goal is to modify an old anti-cancer drug that shows strong efficacy but is too toxic, especially for the gut, to be clinically developed
.
" For this, we used a pro-drug approach
.
The uniqueness of our approach is that we utilize a novel chemical design to create a prodrug that simultaneously has biological activation in cancer cells, but this priority targeting cancer cell payload in healthy tissues such as the gut now enables this class of effective drugs to be safely re-evaluated in humans.
"

The newly modified prodrug takes advantage of a common property in cancer cells: an appetite for an amino acid called glutamine, a key component
of proteins, lipids and nucleotides, as well as energy formation.
Fast-growing cancer cells use large amounts of glutamine, a phenomenon known as "glutamine addiction," but other healthy cells that rotate quickly, such as those in the gut, also rely on glutamine
.

Co-author Dr.
Rana Rais said: "DRP-104 is a tumor target prodrugDiazo-5-O xo-L-n of glutamine-mimicking drug DON(6-), which inhibits multiple glutamine-taking enzymes
in cancer cells.
Many early studies of DON showed that it was highly effective in both humans and mice, but its development was halted
due to its toxicity to normal tissues, especially the gut.
”

It wasn't until Slusher, Rais and their team decided to chemically modify DON that development of such promising drugs resumed
.

"We added a chemical group called a promoter group to the DON and inactivated it in the body until it reached the tumor, where the promoter group was cut away by enzymes that are abundant in the tumor but not in the gut," said Slusher, a member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg Kimmel Cancer Immunotherapy Institute
。 ”

In the new study, the researchers injected the original DON drug and the enhanced DRP-104 drug into mice implanted with tumors
.
In mice treated with DRP-104, the researchers found that the drug activity in tumors was 11 times
higher than in the gastrointestinal tract (intestine).
Both drugs completely wiped out the tumor, but DON was more intestinally toxic to mice than DRP-104
.

Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals, which licenses the new precursor for clinical development
.
DRP-104 is undergoing Phase I/II clinical trials across the United States, including Johns Hopkins University Gimir Cancer Center, for patients with
advanced solid tumors.
Slusher said her Johns Hopkins Drug Discovery Lab is also actively looking for other drugs
that have failed in clinical trials due to toxicity issues.
They hope to apply this prodrug design to
drugs that treat other diseases.

The study was funded by the National Cancer Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, R01CA193895, R01CA229451, R01NS103927, R01CA226765, Bloomberg Kammel Cancer Immunotherapy at Johns Hopkins and CureSearch for Childhood Cancer
.