Stopping Enzyme EZH2 Could Help Many Mesothelioma Patients

Drugs that disrupt the workings of the enzyme EZH2 could prove effective in stopping the growth of mesothelioma cells in as many as 60 percent of mesothelioma patients.

Researchers at Memorial Sloan Kettering Cancer Center in New York say the drugs are now in various stages of development, but for uses other than the treatment of mesothelioma.

The researchers unveiled their thinking about enzyme EZH2 in the journal Nature Medicine. In their article, they described the results of an investigation into the BAP1 gene mutation.

It was their work with the BAP1 gene that led them to their discovery concerning EZH2. Basically, EZH2 levels rise when the BAP1 normal functioning is disrupted by mutation.

The researchers determined that this increase in EZH2 is responsible for the wild growth of mesothelioma cells after BAP1 had mutated.

Blocking EZH2 Ends Tumor Growth

They showed all this with the aid of mouse models and mesothelioma cell specimens. Using these, the researchers were able to demonstrate that EZH2 when blocked could halt tumor growth.

The way they blocked EZH2 was by introducing drugs that affected the enzyme’s foundational proteins called histones. Histones supply the information a cell needs in order to operate correctly and stay alive.

It turns out that too much EZH2 is produced if the information disseminated by histones is corrupted because the histones themselves are corrupted.

Here’s what the researchers themselves had to say about all this. “BAP1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets.”

Not only that, but they said “[c]onditional deletion of BAP1 and EZH2 in vivo abrogates the myeloid progenitor expansion induced by BAP1 loss alone.”

According to the researchers, loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1), but that this is “consistent with a role for H4K20me1 in the transcriptional regulation of EZH2.”

For the record, they also said the expression of SETD8-the H4K20me1 methyltransferase reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells.

Therefore “mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies,” the researchers concluded.

Mesothelioma and Epigenetic Changes

EZH2-blocking drugs aren’t yet widely available. A few are in the early phases of clinical trials. Most are still being developed in the lab.

The one thing true of all of them is that they are designed to bring about epigenetic changes within cancer cells.

Epigenetic changes are those that occur at the gene level but not via the workings of the DNA code. As scientists have discovered, some altered gene traits are passed from parent cell to child cell without the occurrence of any alteration to the DNA code.

Some of this is perfectly normal. For instance, stem cells rely on epigenetic changes to spin off next-generation cells that are more specialized than the parent cells.

But some of this is totally abnormal. The result is cancer. And, under certain conditions, the cancer is mesothelioma.

The researchers indicate they will next be looking to translate their findings into practical applications. For that they have teamed up with a biotechnology firm that specializes in epigenetic products.

As one of the researchers stated, “There’s a biological rationale for why these drugs would work in mesothelioma.” He added that he sees this as potentially being “a tremendous innovation for patients.”