An epigenetic drug currently used for the treatment of blood cancers and rare sarcomas can stop the growth of bladder cancer by activating the immune system, reports a new study from Northwestern Medicine in mice.
This is the first time that a drug used in rare hematological malignancies and sarcomas has been used to treat one of the most common solid tumours. The drug, tazemetostat, was originally developed to treat lymphoma.
“We found for the first time that the drug actually works by activating the immune system, not just inhibiting the tumor,” said the study’s lead author, Dr. Joshua Meeks, associate professor of urology, in Biochemistry and Molecular Genetics at Northwestern. Feinberg University School of Medicine and Northwestern Medical Physician/Scientist.
The study will be published on October 5 in Scientists progress.
“We think the specific mutations that may make the drug effective are found in nearly 70% of bladder cancers,” said Meeks, also a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
Bladder cancer affects more than 700,000 people in the United States. It is the sixth most common cancer overall and the fourth in men. More than 80,000 people in the United States are diagnosed with bladder cancer each year.
“Survival for advanced bladder cancer is extremely low, and the drug works through different mechanisms than any other treatment,” Meeks said. “This is the first application of epigenetic therapy in bladder cancer. »
The drug is a well-tolerated pill and could be added to other systemic therapies for bladder cancer, Meeks said. It is currently being tested in a nationwide clinical trial being conducted by Northwestern researchers for patients with advanced bladder cancer.
Northwestern researchers have shown that the drug, which targets the EZH2 gene – abundant in most tumors – can stop the growth of bladder cancer.
“EZH2 is typically overexpressed in most solid tumors and works by ‘locking’ tumors into a growth state,” Meeks said. “We think this is one of the main genes involved in cancer. We were interested in this gene because the most common mutations in bladder cancer can make EZH2 more active. When cells have higher levels of activity of this gene, they proliferate. »
When scientists knocked out EZH2 in bladder cancers in mice, the tumors were much smaller and filled with immune cells.
“That was our clue that the immune system might be suppressed by EZH2,” Meeks said. “Then we gave a commercially available drug (tazemetostat) to inhibit the activity of this gene. This caused the bladder to become stuffed with many immune cells. Finally, when we used mice without T-cells, we found the drug to be ineffective, confirming that the immune system was likely the drug’s primary pathway of action.
“We find that the treatment is a powerful immunotherapy in translational research. The drug modifies the tumor to prime the immune system, activating CD4 helper cells that coordinate the immune response and recruit more T cells.”
Other Northwestern authors include Andrea Piunti (now a faculty member at the University of Chicago Medical Center) Ali Shilatifard, Stephen Miller, and Lu Wang.
The United States Veterans Affairs Research and Development Office funded the translation work (grant 5I01BX003692-06) and the National Cancer Institute, National Institutes of Health, and Lurie Comprehensive Cancer Center funded the clinical trial.
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Materials provided by Northwestern University. Note: Content may be edited for style and length.