Epigenetic drug used to treat blood cancers, rare sarcomas, may stop the growth of bladder cancer

Epigenetic drug used to treat blood cancers, rare sarcomas, may stop the growth of bladder cancer

An epigenetic drug currently used to treat blood cancers and rare sarcomas can stop the growth of bladder cancer by activating the immune system, a new Northwestern Medicine study in mice reports.

It is the first time that a drug used to treat hematological malignancies and rare sarcomas has been used to treat one of the most common solid tumors. The drug tazemetostat was originally developed to treat lymphoma.

“We discovered for the first time that the drug actually works by activating the immune system and not just inhibiting the tumor,” said lead study author Dr. Joshua Meeks, associate professor of urology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine and a physician-scientist at Northwestern Medicine.

The study will be published Oct. 5 in Science Advances.

“We believe that the specific mutations that could make the drug successful 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 most common in men. More than 80,000 people are diagnosed with bladder cancer each year in the United States.

The survival rate for advanced bladder cancer is extremely low and the drug works by different mechanisms than any other therapy. This is the first application of epigenetic therapy to bladder cancer.”

Dr. Joshua Meeks, lead author of the study

The drug is a pill that is well tolerated and can be added to other systemic therapies for bladder cancer, Meeks said. It is currently being tested in patients with late-stage bladder cancer in a national clinical trial led by researchers at Northwestern.

Northwestern researchers showed that the drug, which targets the EZH2 gene –; abundant in most tumors -; can stop the growth of bladder cancer.

“EZH2 is commonly overexpressed in most solid tumors and causes tumors to become ‘locked’ in a growth stage,” Meeks said. "We believe it is one of the main genes involved in cancer. We were interested in this gene because the most common mutations in bladder cancer may make EZH2 more active. When cells have higher levels of activity of this gene, they proliferate."

When scientists knocked out EZH2 in bladder cancer in mice, the tumors were much smaller and full of immune cells.

“That was our clue that the immune system might be suppressed by EZH2,” Meeks said. "Next, we gave a commercially available drug (tazemetostat) to inhibit the activity of this gene. It caused many immune cells to clog the bladder. Finally, when we used mice without T cells, we found that the drug was ineffective. This confirms that the immune system is likely the primary pathway through which the drug works.

"In translational research, we are finding that the treatment is an effective immunotherapy. The drug modifies the tumor to stimulate the immune system by activating CD4 helper cells, which 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 US Veterans Affairs Office of Research and Development funded the translational work (grant 5I01BX003692-06), and the National Cancer Institute, National Institutes of Health, and Lurie Comprehensive Cancer Center funded the clinical trial.

Source:

Northwestern University

Reference:

Piunti, A., et al. (2022) Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma. Scientific advances. doi.org/10.1126/sciadv.abo8043.

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