Johns Hopkins Medicine researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissue intact. Scientists have dubbed this type of targeted approach “prodrugs” — drugs designed to release their payload in a specific area of the body and no other areas. A prodrug discovered by Johns Hopkins, called DRP-104 (sirpiglenastat), is in early clinical trials in people with advanced solid tumors. Recently published studies in mice show that the supplemented drug preferentially eliminates cancer cells, but does not harm healthy cells.
The report on their experiments was published on November 16 in Achievements of science.
“Our goal was to modify an old cancer drug that showed high efficacy but was too toxic, especially to the gut, to be developed clinically. For this we used a prodrug. The uniqueness of our approach is that we used novel chemical design to create a prodrug that was both bio-activated in cancer cells, but bio-inactivated in healthy tissues such as the intestine. This preferential targeting of the payload to cancer cells now allows us to safely reevaluate this effective class of drugs in humans,” says study author Barbara Slasher, PhD, MAS, director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience , Medicine and Oncology at the Johns Hopkins University School of Medicine.
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, and for generating energy. Fast-growing cancer cells use huge amounts of glutamine, a phenomenon called “glutamine addiction,” but other healthy cells with fast turnover, such as the cells that line the intestines, also depend on glutamine.
Co-author Rana Rice, Ph.D., associate professor of neuroscience and pharmacology, says, “DRP-104 is a tumor-targeted prodrug of a glutamine-mimicking drug called DON (6-Diazo-5-Oxa-L-norleucine), which inhibits many glutamine-using enzymes in cancer cells. Many early studies of DON showed that it was very effective in humans and mice, but its development was halted because of its toxicity to normal tissues, especially the intestine.’
Development of this promising drug class did not resume until Slusher, Reiss, and team decided to make chemical modifications to DON.
“We added chemical groups called promoters to DON that made it inactive in the body until it reached the tumor, where the promoters were cleaved off by enzymes that are abundant in the tumor but not in the gut,” says Slasher, who is a member of the Cancer Center Johns Hopkins Kimmel and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. “This special design of the prodrug made DON target the target (the tumor) and had less of an effect on healthy cells elsewhere.”
For the new study, the researchers gave the original drug DON and the extended drug DRP-104 to mice with implanted tumors. In mice that received DRP-104, the researchers found 11 times more active drug in the tumor compared to the gastrointestinal tract (gut). Both drugs completely destroyed the tumor, but DON caused more intestinal toxicity in the mice than DRP-104.
Slusher and study co-authors Rana Rice, Pavel Majer and Jonathan Powell co-founded the biotech company Dracen Pharmaceuticals Inc, which licensed this new prodrug for clinical development. DRP-104 is in Phase I/II clinical trials at sites across the US, including the Johns Hopkins Kimmel Cancer Center, for people with late-stage solid tumors. Slasher says her Johns Hopkins Drug Discovery lab is also actively looking for other drugs that have not passed clinical trials because of toxicity concerns. They hope to apply this same prodrug to drugs for other diseases.
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 Johns Hopkins Cancer Immunotherapy, and CureSearch for Children with Cancer.
Additional Johns Hopkins study authors: Kathryn Lemberg, Lukasz Tenaro, Matthew Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie Aguilar, Liang Zhao, Diane Peters, Carolyn Tallon, Rajeev Pandey, Ajit Thomas, Ranjit Desh, Tangi Seiwert, Robert Leone, and Jonathan Powell. Pavel Mayer from the Academy of Sciences of the Czech Republic.
Slusher, Rice, Tenaro, Majer, Alt, and Powell are inventors on Johns Hopkins University patents covering the novel glutamine antagonist prodrugs described in this study. These patents were licensed to Dracen Pharmaceuticals Inc. Slusher, Rice, Majer, and Powell are founders and own equity in Dracen Pharmaceuticals Inc. Slusher also serves as a scientific advisor to Dracen. Pursuant to the license agreement between Dracen Pharmaceuticals, Inc. and Johns Hopkins University, the university has the right to share royalties related to the technology cited in the research and referenced in this story.
This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policy.