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In order to support its uncontrolled growth, tumors devour large amounts of nutrients. For decades, scientists have been trying to develop drugs that cut off the “food” supply of tumors.

 

On November 7, a recent study published in the journal Science, the team from the Johns Hopkins Cancer Immunotherapy Bloomberg-Kimmel Institute revealed that an upgraded version of an anticancer drug that failed in the past could not only block tumor cells. Obtaining an essential nutrient can also stimulate immune cells to inhibit cancer cell growth.

 

In fact, cancer cells “greedy” not only provide vital molecules for their survival and replication, but also turn the surrounding environment into an acidic, hypoxic state, preventing immune cells from destroying them. An amino acid called glutamine is one of the many nutrients needed for many tumors.

 

Since the 1950s, researchers have attempted to target this dependence of glutamine on tumors and develop drugs that block their metabolism. Among them, a compound named DON (6-diazo-5-oxo-L-norleucine, a glutamine antagonist) derived from bacteria has been confirmed in preclinical studies to inhibit cancer cells from utilizing glutamine. A variety of enzymes to kill tumors. However, unfortunately, in clinical trials, the drug caused severe nausea and vomiting and has not been approved for marketing.

 

Chemical structure of DON and JHU083

In this newly published study, Jonathan Powell, an immunologist at the Johns Hopkins School of Medicine, and colleagues developed a new version of DON, JHU083 (Ethyl 2-(2-Amino-4-methylpentanamido), which may be more easily accepted by the stomach. )-DON). Compared to the original DON, JHU083 carries two chemical groups that remain inert until it reaches the vicinity of the tumor. Upon reaching the vicinity of the tumor, enzymes that typically wander around the tumor remove these “molecular handcuffs” (ie, chemical groups), releasing the drug and killing the cancer cells.

 

“With this approach, the vast majority of active drugs can reach our target,” Powell said.

Anti-tumor effect of JHU083
To test the anti-cancer activity of JHU083, the Powell team first injected four types of cancer cells (MC38 colon cancer cells, EL-4 lymphoma cells, CT26 colon cancer cells, and B16 melanoma cells) into mice to induce tumors. They then treated some of these cancer mice with JHU083. It was found that this new version of DON is effective against all four tumors and can significantly inhibit tumor growth and improve survival in mice. For example, in untreated mice, colon cancer tumors increased more than 5-fold after about 3 weeks, but in mice treated with JHU083, the tumors shrank and almost disappeared.

 

JHU083 in combination with PD-1 antibody

The study also investigated the combination of JHU083 and PD-1 antibodies and found that simultaneous administration of both drugs induced the most effective anti-tumor response. Compared with PD-1 antibody monotherapy, the combination of JHU083+PD-1 antibody in tumor-bearing mice significantly improved the anti-tumor effect: in the MC38 colon cancer model, the complete response rate of the combination treatment group was close to 100% (PD) -1 antibody monotherapy group, no mice achieved complete remission).

 

In terms of mechanism of action, the scientists found that JHU083 not only inhibits glutamine metabolism, but also disrupts other aspects of cell biochemistry, such as the ability to utilize glucose. Even more surprisingly, JHU083 also enhances the ability of T cells to destroy cancer cells.

Relative activity pattern of basal metabolic pathways in highly proliferating cells, glutamine-inhibited MC38 cancer cells, and glutamine-inhibited effector CD8+ T cells

Often, scientists worry that drugs that target the metabolism of cancer cells can also poison normal cells, including anti-tumor T cells. But in this study, Powell et al. found that T cells deprived of glutamine by JHU083 turned to an alternative source of raw materials needed to synthesize DNA and other key molecules, but tumor cells do not. Researchers believe that this suggests that glutamine is expected to be a “metabolic checkpoint” for cancer immunotherapy.

Stimulated by a new drug, T cells (purple) pounce on cancer cells (yellow)

 

According to Ji Zhang, a cancer biologist at Indiana University, the findings of Powell et al. are surprising because their papers show for the first time that T cells and cancer cells respond differently to glutamine inhibition.

 

Ralph DeBerardinis, a cancer biologist at the University of Texas Southwestern Medical Center, also believes that the new results are compelling because only one drug is needed to induce two anti-cancer mechanisms: starving the tumor “, and enhance the role of immune cells.

 

It is reported that the Powell team will conduct JHU083 human body safety testing next year. If the clinical trial data is positive, the drug will become a new type of anticancer therapy.

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