A commonly used anti-rejection drug could be reused to treat certain liver cancers

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<div data-thumb = "https://3c1703fe8d.site.internapcdn.net/newman/csz/news/tmb/2019/commonlyused.jpg" data-src = "https://3c1703fe8d.site.internapcdn.net/ newman / gfx / news / hires / 2019 / commonused.jpg "data-sub-html =" Mouse liver tissue showing cells surrounding the central vein with mTOR active substance (red) and glutamine synthetase (green) present in the same cells (yellow)). Cell reports/ University of Pittsburgh ">

Research on Animal Models and Patient Tissues by the University of Pittsburgh School of Medicine uncovers a new molecular pathway in the liver suggesting the use of a commonly used anti-rejection drug to treat certain liver cancers.

"What we have discovered is that liver cancers with a specific mutation in the β-catenin gene are probably more susceptible to rapamycin, an anti-rejection drug commonly used in transplantation," Satdarshan said. Monga, MD, professor of pathology and founder. director of the Pittsburgh Liver Research Center of the Pitt School of Medicine and lead author of the study published in Cell metabolism. "We think this gives us a new approach to precision medicine for developing liver cancer treatments, which are often very resistant to treatment."

The current study began when Monga and his team made a chance observation that a ring of cells surrounding the central vein, a blood vessel found in the liver, had elevated levels of a protein called mTOR. The active protein mTOR, a sensor of nutrition and energy essential for cellular metabolism, was found in the same cells where β-catenin was known to be active.

About 20 to 35% of liver cancers have β-catenin mutations, but it is unclear how and why these mutations could contribute to cancer cell growth. Thus, when Monga discovered similar high levels of active mTOR in β-catenin-mutated liver cancers, he wondered whether the two proteins could be functionally related.

To determine the origin of mTOR activation, scientists created a mouse model of liver cancer in which they genetically mutated β-catenin, as well as another gene called Met, specifically in liver cells. These mice developed liver cancers genetically very similar to those observed in humans.

Starting from an increased activation of mTOR, they followed the molecular crumb of these mice to show that β-catenin activated mTOR through an intermediate enzyme called glutamine synthase (GS). This molecular pathway was related to energy intake, as fast-growing cancer cells, which consume more energy than normal cells, exhibited higher activity of GS and mTOR.

"I like to say that these tumors are dependent on mTOR," said Monga, also a researcher at the Regenerative Medicine Institute McGowan and at the Hillman Cancer Center at UPMC. "The activation of mTOR activates the protein manufacturing plants in these cells, giving them the resources to divide and grow."

When genetically modified mice were fed rapamycin, an immunosuppressant that inhibits mTOR, the tumor size decreased and when they added another drug inhibiting Met, the tumors were almost completely eliminated, which shows that mTOR has played an important role in the growth of these tumors. .

The researchers noted that an earlier clinical trial in patients with liver cancer had not revealed any significant interest in rapamycin, but new findings suggest that if the group was limited to patients with β-catenin and mTOR-related tumors, the treatment have been more successful.

"Current liver cancer treatments only increase survival by 3 to 4 months, so taking a precision medicine approach to identify the right patient may help refocus existing drugs to improve success." treatment, "said Monga.

In addition to treating liver cancer, the study also suggests ways to reduce the risk of cancer recurrence in some patients undergoing liver transplantation.

"While transplant patients are prescribed either rapamycin or a different immunosuppressant, those with β-catenin-mutated tumors and mTOR dependence could benefit from the use of rapamycin as a Anti-rejection drug of choice We hope to conduct clinical trials soon to test rapamycin, both in the treatment of liver cancer and in the prevention of its recurrence in patients receiving a liver transplant, "said Monga.

You will find a complete list of all authors of the study in the article online.

Provided by
University of Pittsburgh