Princeton team disables long-term target genes behind major cancer epidemics

A mysterious way in which cancer spreads throughout the body, a process known as metastasis, can make it a very difficult enemy to keep it away. Researchers at Princeton University working in this area have been pulling specific threads for over 15 years, focusing on a single gene that is central to the ability of most major cancers to metastasize. They have now discovered what they describe as a “silver bullet” in the form of compounds that can invalidate this gene in mouse and human tissues. Clinical trials may not be too far away.

Metastatic cancer is, in fact, the leading cause of death from the disease, so it is an important focus and good reason for researchers. Surgery and chemotherapy may be effective in removing the first tumor, but broken cells can carefully pass around the body and cause new tumors months or years later.

“Metastatic breast cancer causes more than 40,000 deaths each year in the United States, and patients do not respond well to standard therapies such as chemotherapy, targeted therapies, and immunotherapy,” says Princeton behind the new discovery. Minhong Shen, a member of the team, said. “Our study has identified a range of compounds that can significantly increase the response rate of chemotherapy and immunotherapy in a mouse model of metastatic breast cancer. These compounds have significant therapeutic effects.”

This discovery stems from a 2004 study in which Princeton scientists identified a gene called metadherin (MTDH) associated with metastatic breast cancer. A 2009 paper by cancer biologist Yibin Kang found that genes were amplified to produce abnormally high levels of MTDH protein in about one-third of breast cancer tumors, the process of metastasis, as well as the center of resistance of those tumors. But I showed that it happened. chemical treatment.

“I had a lot of excitement,” says Kang. “Wow, we found a metastatic gene associated with poor patient outcomes! What’s next? Can we target it?” That was a big question. At the time, no one knew how this vague and lesser-known gene would work. There was no similarity to other known human proteins. I didn’t know if it was important for normal physiology. “

Subsequent studies continued to shed light on the importance of the MTDH gene and showed how important it is for cancer to prosper and metastasize. Mice designed to lack the gene grew normally, mice with breast cancer had far fewer tumors, and the formed tumors did not metastasize. Later, this turned out to be true for prostate cancer, lung cancer, colorectal cancer, liver cancer, and many other cancers.

“So, basically, in most major human cancers, this gene is essential for cancer progression and all the terrible things associated with cancer, but it still doesn’t seem to be important for normal development,” Kang said. Says. “We knew that this would be an excellent drug discovery target because mice can grow, reproduce and live normally without this gene.”

The crystal structure of MTDH indicates that the protein has a pair of protrusions that are likened to a finger. It works with two holes on the surface of another protein called SND1. According to Kang, this is “like two fingers stuck in a hole in a bowling ball,” and scientists say that if this close relationship breaks, the harmful effects of MTDH will be diminished. I thought it could be very useful.

“I knew the shape of the keyway from the crystal structure, so I kept looking until I found the key,” says Kang.

The team screened for the right molecules to fill these holes for two years before arriving at what was called the “silver bullet,” with no major success. The resulting compound closes these voids, prevents protein interlocking, and provides a potent anti-cancer effect similar to that seen in previous studies in MTDH-deficient mice.

“In 2014, we showed what happens when we knock out a gene at birth,” says Kang. “This time we show that the function of this gene can be eliminated after the tumor has already developed into a completely full-blown life-threatening cancer. Genetically or pharmacologically it using our compound. It turns out that you achieve the same result whether you do it or not. “

Scientists say MTDH helps cancer in two main ways: helping the tumor tolerate the stress of chemotherapy and turning off the alarm that the organ normally sounds when the tumor invades the cancer. say. By working with the SND1 protein, it hides the immune system from recognizing the danger signals normally produced by cancer cells and thus prevents them from attacking them.

“Now with this drug, we reactivate the alarm system,” says Kang. “This is essentially why MTDH is not essential for normal tissue, as healthy cells are not normally stressed or present with signals that are perceived as foreign by the immune system. MTDH is a typical “cancer adaptation gene” and is uniquely needed for malignant cells to survive and prosper. “

The team is currently working on compound purification in the hope of improving the effect of breaking the connection between MTDH and SND1 and reducing the required dosage. They want to be ready for clinical trials in human patients in a couple of years, noting that they are only scratching the surface in terms of what it can do. ..

“Two papers published today in a row identify compounds, show that they are effective against cancer, and show that they are very effective when combined with chemotherapy and immunotherapy. “We do,” said Kang. “Metastatic cancers are horrifying, but they can be attacked and treated by understanding how they work, that is, their dependence on certain important pathways such as MTDH. You can make it easier to receive. “

The study was open to the public Two papers In the journal Nature Cancer..

sauce: Princeton University Princeton team disables long-term target genes behind major cancer epidemics

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