An epigenetics drug could be effective in treating bladder cancer

A new study conducted by Northwestern University researchers has demonstrated that an epigenetics drug that is used for the treatment of blood cancers and epithelioid sarcoma can prevent the growth of bladder cancer by activating the immune system.

It's the first time a medication for uncommon sarcomas and hematologic cancers has been used to treat one of the most prevalent solid tumors. The medicine named tazemetostat was first developed to treat lymphoma.

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

"We think the specific mutations that may make the drug successful are found in almost 70% of bladder cancers."

Bladder cancer is the sixth most prevalent cancer

More than 700,00 people are suffering from bladder cancer in the U.S., and more than 80,000 in the U.S. are diagnosed with bladder cancer yearly. It is the fourth most prevalent cancer in men and the sixth most prevalent cancer overall.

"Survival for advanced bladder cancer is extremely poor, and the drug works by mechanisms different than any other therapy," told Meeks. "This is the first application of epigenetic therapy in bladder cancer."

The drug is currently being tested for people with late-stage bladder cancer in a national clinical trial conducted by Northwestern University scientists. The research also showed that the drug, which targets the EZH2 gene, stops the growth of bladder cancer efficiently.

"EZH2 is commonly overexpressed in most solid tumors and works by 'locking' tumors in a state of growth," Meeks added. "We think it's one of the main genes involved in cancer. We were interested in that gene because the most common mutations in bladder cancer may make EZH2 more active. When cells have higher levels of this gene activity, they proliferate."

When scientists tested tazemetostat on mice, the drug appeared to knock out EZH2 in bladder cancer tumors, and in the end, the tumors were considerably smaller and contained more immune cells.

"That was our clue the immune system may be suppressed by EZH2," Meeks said. "Next, we gave a commercially available drug (tazemetostat) to inhibit the activity of this gene. It caused a lot of immune cells to pack the bladder. Finally, when we used mice with no T cells, we found the drug was ineffective, confirming that the immune system was likely the primary pathway by which the drug works."

"We find that the treatment is potent immunotherapy in translational research. The drug changes the tumor to prime the immune system, activating CD4 helper cells that coordinate the immune response and recruit more T cells."

The study was published in the journal Science Advances.

Abstract:

The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.