The increased drug kills cancer cells without causing toxicity

Johns Hopkins Medicine researchers have revamped a cancer drug to better target cancer cells and leave healthy tissue intact. Scientists have dubbed this type of targeted approach a “prodrug,” a drug designed to deliver its payload to a particular area of ​​the body and nowhere else. The prodrug being discovered by Johns Hopkins, called DRP-104 (sirpiglenastat), is in early stage clinical trials in people with advanced solid tumors. Recently published studies in mice show that the boosted drug preferentially kills cancer cells but does not harm healthy cells.

A report of their experiments was published on November 16 in The progress of science.

“Our goal was to modify an older cancer drug that had shown strong 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 used a new chemical project to create a prodrug that was simultaneously bio-activated in cancer cells but bio-inactivated in healthy tissues such as the intestine. This preferential targeting of the payload to cancer cells is now allowing this effective class of drugs to be safely re-evaluated in people,” says study author Barbara Slusher, Ph.D., MAS, director of Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience, medicine and oncology at Johns Hopkins University School of Medicine.

The newly modified prodrug exploits a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a building block for proteins, lipids and nucleotides, as well as for energy formation. Fast-growing cancer cells use up enormous amounts of glutamine, a phenomenon called “glutamine addiction,” but other healthy cells with rapid turnover, such as those lining the intestines, also rely on glutamine.

Co-author Rana Rais, Ph.D., an associate professor of neurology and pharmacology, 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 that it was strongly effective in people and mice, but its development has been halted due to its toxicity to normal tissue, particularly the l ‘intestine.

Development of this promising class of drugs didn’t resume until Slusher, Rais, and team decided to make chemical modifications to DON.

“We added chemical groups, called promoieties, to DON that made it inactive in the body until it reached the tumor, where the promoieties were cut by enzymes that are abundant in the tumor but not in the gut,” Slusher says. who is a member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. “This specific prodrug design made DON target its intended target (tumor) and have less impact on healthy cells elsewhere.”

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

Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals Inc, which has licensed this new prodrug for clinical development. DRP-104 is in Phase I/II clinical trials at sites across the United States, including the Johns Hopkins Kimmel Cancer Center, for people with advanced stage solid tumors. Slusher says his Johns Hopkins Drug Discovery lab is also actively looking for other drugs that have failed clinical trials due to toxicity concerns. They hope to apply this same prodrug design to medicines for other conditions.

This research was funded by the National Cancer Institute of the National Institutes of Health and the National Institute of Neurological Disorders and Stroke R01CA193895, R01CA229451, R01NS103927, R01CA226765, Bloomberg Kimmel for Cancer Immunotherapy at Johns Hopkins, and CureSearch for Children’s Cancer.

Other Johns Hopkins study authors include Kathryn Lemberg, Lukáš Tenora, Matthew Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie Aguilar, Liang Zhao, Diane Peters, Carolyn Tallon, Rajeev Pandey, Ajit Thomas, Ranjeet Dash , Tanguy Seiwert, Robert Leone and Jonathan Powell. Pavel Majer is from the Academy of Sciences of the Czech Republic.

Slusher, Rais, Tenora, Majer, Alt, and Powell are the inventors of the Johns Hopkins University patents covering the new glutamine antagonist prodrugs described in this research. These patents have been licensed to Dracen Pharmaceuticals Inc. Slusher, Rais, Majer and Powell are the founders and hold interests in Dracen Pharmaceuticals Inc. Slusher also serves as a scientific advisor to Dracen. Under a licensing agreement between Dracen Pharmaceuticals, Inc. and Johns Hopkins University, the University is entitled to royalty distributions related to the technology named in the study and referenced in this story.

This agreement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies.

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