Love-hate' anti-cancer drugs, only against cancer cells, inactivated in healthy tissues!

In response to the characteristics of "glutamine addiction" in energy metabolism of cancer cells, DON, a drug with a highly similar structure to glutamine, can selectively block multiple reactions involved in glutamine, "starving" tumor cells. In the first clinical studies, DON showed good efficacy, but discontinued the study due to its high toxicity to gastrointestinal tissue. Now, researchers at Johns Hopkins University have designed a drug precursor for DON that activates only in cancer cells and is inactivated in healthy tissue.

The old saying "three poisons of medicine" dialectically illustrates the complex relationship between the efficacy and side effects of drugs. As far as general drugs are concerned, after entering the human body, only a very small part of them usually act on the lesion site, which not only limits the efficacy of the drug, but also brings about the toxic side effects of the drug. 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 anti-tumor drugs, people always hope that drugs can kill cancer cells accurately enough to be harmless to normal healthy cells. In 1913, Nobel laureate German scientist Paul Ehrlich proposed the concept of a "Magic Bullet", which envisaged the selective delivery of cytotoxic drugs to tumor sites. In 1958, the Australian authority on medicinal chemistry development Adrien Albert proposed the concept of "prodrug" (Prodrug) is another solution, that is, let the inactive or very low activity of the precursor drug in the body metabolize and then transform into an active drug, improve the speed and degree of drug absorption into the human circulation, improve targeting, reduce toxic side effects.

How cancer cells become cancer cells

In 2000, American oncologist Professor Robert A. Weinberg and American biologist Professor Douglas Hanahan published the first edition of the review "Hallmarks of Cancer" describing the characteristics of tumor cells in Cell, which has been cited nearly 40,000 times so far, which is the bible in the field of tumors. In the paper, they propose 6 acquired characteristics, namely:

Self-Sufficiency in Growth Signals

Insensitivity to Antigrowth Signals

■ Evading apoptosis

Limitless Replicative Potential

■ Sustained Angiogenesis

■ Tissue invasion and metastasis.

In 2011, they published a second edition of "Hallmarks of cancer: next generation" in Cell, which once again became a classic in the field of oncology, with more than 63,000 citations. On top of the first version of the cancer features, they added four new features:

Avoiding Immune Destruction

■ Tumor-Promotion Inflammation

■ Deregulating Cellular Energetics

Genome Instability and Mutation

Each of the 10 characteristics of tumors that are different from normal cells can be targeted for treatment.

In January, at Cancer Discovery, Douglas Hanahan published a third edition of "Hallmarks of Cancer: New Dimentions," adding four new features

Unlocking phenotypic plasticity

Nonmutational Epigenetic Reprogramming

Polymorphic microbiomes

Senescent Cells

"Can't stop" glutamine

Among these characteristics of tumor cells, the metabolic activity of cancer cells that is different from normal cells is called the "Warburg effect", which uses the glycolytic pathway that normal cells use under anaerobic conditions to "ferment" glucose into lactic acid.

To maintain normal mitochondrial function, cancer cells rely on other nutrients to meet the tricarboxylic acid cycle through the replenishment process, synthesizing 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 also plays an important role in the invasion of tumor cells.

In response to this phenomenon, scientists began to think about whether it could play an anti-cancer role if the source of glutamine of the tumor was cut off. What's even more exciting is that many types of tumors are dependent on glutamine, which means that drugs developed for this mechanism are expected to become a broad-spectrum anti-cancer drug.

"The Return of the King" DON

DON is such a glutamine analog isolated from Streptomyces, which can inhibit a variety of enzymes that use glutamine in cancer cells, causing cancer cells to "starve to death", while also enhancing the cytotoxicity of T cells in the tumor microenvironment. DON has been shown to have anti-cancer efficacy in both mouse and human trials, but unfortunately, certain rapidly renewing healthy cells, such as cells lining the gut, also rely on glutamine. This makes DON also show toxicity in healthy gastrointestinal tissues, causing adverse reactions such as mucositis, diarrhea, gastric bleeding, etc., and finally abandoned for clinical development.

To this end, Johns Hopkins researchers decided to chemically modify DON and add some "precursor groups" to it to lose its original activity, turning it into a tumor target precursor drug DRP-104, which can be cut off by enzymes that are rich in tumors but not in the gut, so that the drug can better target cancer cells without damage to healthy tissue. The results of the study, titled "Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug," were published in Science Advances on November 16, 2022 [4].

In mouse trials, the researchers found that compared with mice with tumors treated with DON and DRP-104, the active drug dose in the tumor was 11 times that of the gastrointestinal tract and 6 times that of plasma, which enabled tumor regression in the absence of gastrointestinal side effects. In addition, the researchers found that DRP-104 can enhance the efficacy of anti-PD-1 immunotherapy in a CD8+ T cell-dependent manner. Not only that, mice cured with DRP-104 monotherapy were able to resist the re-attack of the tumor, indicating that the method can build immune memory. DRP-104 also outperformed tumor targeting in comparison with JHU-083, another DON precursor drug previously developed by the research team.

Dr. Barbara Slusher, author of the study and director of the drug discovery program at Johns Hopkins University, said similar precursor drug designs are expected to be applied to other drugs that have failed clinical trials due to toxicity issues. At the same time, DRP-104, with its excellent performance in preclinical trials, has also entered phase I/II clinical trials throughout the United States, and is expected to be used as a single drug or in combination with immunotherapy to treat advanced solid tumors in the future.