Targeting the "glutamine-addicted" properties of cancer cells in energy metabolism, a drug with a highly similar structure to glutamine can selectively block multiple glutamine-involved reactions, "starving" tumor cells. In the first clinical studies, DON showed good efficacy, but the study was discontinued due to its high toxicity to gastrointestinal tissue. Now, researchers at Johns Hopkins University have designed a drug precursor to DON that works only in cancer cells and is inactivated in healthy tissue.
The old saying "a drug is three parts poison" dialectically explains the complex relationship between the efficacy and side effects of a drug. As for general drugs, after entering the human body, usually only a small part of the action on the lesion site, which not only limits the efficacy of drugs, but also brings about the toxic side effects of drugs. In the process of drug development, if the incidence of adverse reactions cannot be limited, it means the failure of drug trials.
Especially in the field of anticancer drugs, the hope is that drugs will kill cancer cells precisely enough to do no harm to normal, healthy cells. In 1913, Nobel Prize-winning German scientist Paul Ehrlich proposed a "Magic Bullet" concept that envisioned the selective delivery of cytotoxic drugs to tumor sites. In 1958, Adrien Albert, an authority on the development of pharmaceutical chemistry in Australia, proposed the concept of "Prodrug", which is another way to solve the problem. That is, the precursor drugs with no or very low activity are metabolized in the body and then transformed into active drugs, so as to improve the speed and degree of drug absorption into human circulation. Improve targeting, reduce toxicity and side effects.
In 2000, American Cancer scientist Professor Robert A. Weinberg and American biologist Professor Douglas Hanahan published the first edition of "Hallmarks of Cancer" in Cell, which describes the characteristics of tumor cells and has been cited nearly 40,000 times. It's the bible of oncology. In the paper, they identified six acquired traits:
■ Self-Sufficiency in Growth Signals
■ Insensitivity to Antigrowth Signals
■ Evading apoptosis
■ Limitless Replicative Potential
■ Sustained Angiogenesis
■ Tissue Invasion and Metastasis.
In 2011, they published the second edition of "Hallmarks of cancer: The next generation" in Cell, which has once again become a classic work in the field of cancer, and has been cited more than 63,000 times. Based on the first version of cancer signatures, they added four new features:
Avoiding Immune Destruction ■ Avoiding immune destruction
■ Tumor-Promotion Inflammation, inflammation and inflammation
■ About Deregulating Cellular Energetics
■ Genome Instability and Mutation
Each of the 10 features of a tumor that are different from normal cells can be a target for treatment.
In January of this year, Douglas Hanahan published the third edition of Hallmarks of Cancer: New Dimentions in Cancer Discovery, with four new features:
Unlocking Phenotypic Plasticity ■ unlocking phenotypic plasticity
■ Nonmutational Epigenetic Reprogramming
■ Polymorphic Microbiomes
■ Senescent Cells
Among these characteristics of tumor cells, the metabolic activity of cancer cells that is different from normal cells is called the "Warburg effect". The energy supply adopts the glycolysis pathway that normal cells only use in the absence of oxygen to "ferment" glucose into lactic acid.
In order to maintain normal mitochondrial function, cancer cells rely on other nutrients to meet the tricarboxylic acid cycle through a backfill process to synthesize lipids, proteins and nucleic acids necessary for tumor growth. Glutamine is the most abundant free amino acid in plasma and becomes the main source of energy for proliferating cancer cells. This phenomenon is also known as the "glutamine addiction" of cancer cells. There is also evidence that glutamine metabolism plays an important role in tumor cell invasion.
In response to this phenomenon, scientists began to wonder whether cutting off the source of glutamine in tumors could have an anti-cancer effect. Even more exciting is the fact that glutamine dependence is present in many types of tumors, which means that the development of drugs targeting this mechanism has the potential to become a broad-spectrum anticancer drug.
DON is one such glutamine analogue isolated from Streptomyces, which can inhibit various glutamine-utilizing enzymes in cancer cells, causing cancer cells to "starve to death", while enhancing the cytotoxicity of T cells in the tumor microenvironment. DON has been shown to have anti-cancer properties in both mice and humans, but unfortunately, certain rapidly renewing healthy cells, such as those lining the gut, also rely on glutamine. As a result, DON showed toxicity even in healthy gastrointestinal tissues, causing adverse reactions such as mucositis, diarrhea and gastric bleeding, and was eventually abandoned for clinical development.
So the Johns Hopkins researchers decided to chemically modify DON, adding "precursor groups" to deactivate it and turn it into a tumor-targeting precursor drug, DRP-104. These precursor groups can be clipped off by enzymes that are abundant in tumors but not in the gut. The drug would then be better able to target cancer cells without harming healthy tissue. The results were published in Science Advances on November 16, 2022 under the title "Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug" [4].
In mice, the researchers found that the active dose of DON versus DRP-104 was 11 times the gastrointestinal dose and 6 times the plasma dose, resulting in tumor regression with no gastrointestinal side effects. In addition, the researchers found that DRP-104 enhanced the efficacy of anti-PD-1 immunotherapy in a way that relied on CD8+T cells. Moreover, the mice cured by DRP-104 monotherapy were able to fend off a reattack of the tumor, suggesting that the method could build immune memory. DRP-104 was also better targeted to tumors than JHU-083, another DON precursor developed by the same team.
Study author Dr. Barbara Slusher, director of the drug Discovery Program at Johns Hopkins University, said there is hope that similar precursor drug designs could be applied to other drugs that have failed clinical trials due to toxicity issues. Meanwhile, DRP-104 has entered phase I/II clinical trials across the United States based on its excellent performance in preclinical trials, and is expected to be used as a single agent or in combination with immunotherapy for the treatment of advanced solid tumors.
