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Prodrugs As a Useful Approach to Targeting Distinctive Aspects of Cancer Metabolism


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Posted 23 November 2022 - 08:11 PM


The goal of cancer research should be to produce a robust, highly effective universal cancer therapy, or as close to universal as possible. One treatment that can be deployed for every type of cancer, with a very good chance of inducing remission. Attempting to tackle cancer subtypes one by one based on their genetic peculiarities is simply not efficient enough to produce meaningful progress in our lifetimes. Further, most cancers are subject to high mutation rates, and in a sizable fraction of patients will prove to be quite capable of evolving immunity to any therapy that targets a non-essential aspect of cancer biochemistry.

Cancer cells as a class are metabolically very different from normal cells; they have to be in order to power the rampant growth characteristic of tumor tissue. This presents a broad area of discovery for the development of prodrugs, molecules in which a toxic drug is amended to become non-toxic in a way that can be reversed by the activity of enzymes present only in the the targeted cell populations. This in principle allows for any usefully toxic chemotherapeutic drug, of which there are many, to be amended into a non-toxic form that will be near entirely processed back into the original toxic drug only by cancer cells. Importantly, at least some prodrug strategies of this nature might be applicable to a broad range of cancers.

Researchers Design 'Prodrug' That Targets Cancer Cells' Big Appetite for Glutamine, Leaving Healthy Cells Unharmed

"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." 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.

"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. 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."

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues.

In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.


View the full article at FightAging




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