A team of scientists at the University of Pittsburgh School of Medicine have recently found that an anti-rejection medication could be used to treat liver cancers. The researchers were studying cells of the liver’s central vein when they happened to happened to make the unique discovery.
The team observed that cells possessing a mutation in the β-catenin gene created excessive amounts of mTOR protein, which they believe leads to cancer development. With many mTOR inhibitors existing on the market, the researchers wanted to see if these drugs could be repurposed to treat cancers in the liver.
To test this hypothesis, the team used a mouse model of liver cancer with β-catenin and MET gene mutations, creating tumors in the liver. Roughly 20-35% of liver cancers have β-catenin mutations, but little is known regarding why these mutations assist the growth of cancer cells.
The team traced molecular activity around increased mTOR activation to determine that β-catenin activated mTOR through the enzyme glutamine synthase. This pathway was tethered to intake of energy, with fast-growing cancer calls consuming more energy and having higher GS and mTOR activity.
“I like to say these tumors are mTOR addicted,” said Satdarshan Monga, M.D., professor of pathology and the founding director of the Pittsburgh Liver Research Center at Pitt’s School of Medicine. Monga is also the senior author of the study, published in Cell Metabolism. “Activating mTOR kicks up the protein-making factories in these cells, giving them the resources to divide and grow.”
When these mice were given rapamycin, an immunosuppressant drug that inhibits mTOR, the tumors decreased in size. When administered another drug that inhibits Met, the tumors were almost completely gone. This supported the researchers’ hypothesis that mTOR plays a key role in tumor development.
The team noted that previous bodies of research in patients with liver cancer found no significant benefit of rapamycin use, but this new work suggests that the drug only helps the 20-35% of liver cancer patients who possess β-catenin mutations. Perhaps if this previous study had focused on individuals with this specific mutation the drug would have more efficiently treated patients.
“Current liver cancer therapies increase the likelihood of survival only by 3 or 4 months, so taking a precision medicine approach to identify the right patient could allow us to repurpose existing drugs to improve treatment success,” said Monga.
Rapamycin treatments are already approved to treat several cancers, including renal cell carcinoma and HER2-negative breast cancer. Monga feels that at the least, his team’s research argues for a liver cancer approach in which transplant patients are given rapamycin as the primary anti-rejection drug over alternatives.
“While transplant patients are prescribed either rapamycin or a different immunosuppressant, those that have β-catenin mutated and mTOR-addicted tumors might benefit from using rapamycin as the preferred anti-rejection medication. We hope to conduct clinical trials in the near future to test rapamycin both in treating liver cancer and to prevent its recurrence in patients receiving liver transplants,” Monga concluded.