Epigenetic Therapy for Mesothelioma

What is Epigenetic Therapy?

Epigenetic therapy uses specially designed drugs to reprogram cancer cells back to a normal, noncancerous state.

Scientists used to think that genetic changes had more of an effect on developing cancer than epigenetic alterations. They now believe that epigenetics may be just as important or even more so in causing cancer.

The difference between genetic mutations and epigenetic changes is simple and complex. In the simplest terms, genetic mutations involve actual changes in our genetic code. Epigenetic changes do not alter our DNA, but rather the expression of our DNA.

Changes to our DNA expression are a normal and natural process. Age, environment, lifestyle, diseases and toxic exposure affect it. For example, scientists know that epigenetics change after asbestos exposure. But they don’t know exactly how this occurs.

Epigenetic Changes in Mesothelioma

A 2010 study found a connection between the number of asbestos fibers in lung tissue and how it affects the changes in our genes. It also showed that these gene changes can help us understand how long people with pleural mesothelioma can survive.

The number of epigenetic changes also helped identify normal tissue from cancerous tissue.

Researchers are hoping to discover ways to harness these epigenetic changes to help find a cure for mesothelioma. A number of clinical trials have tested epigenetic drugs in people with pleural mesothelioma with mixed results. A handful of patients have responded quite well, with one patient entering remission for longer than six years.

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How Epigenetic Therapy Works

This type of treatment works by using medicines to fix any changes in the DNA that might have caused cancer. This helps bring the DNA back to how it was before cancer started.

Scientists have created drugs that can find changes in cancer cells that are related to how the cells grow. This is similar to the way chemotherapy targets rapidly dividing cancer cells. These drugs are sometimes referred to as chemotherapy drugs. Chemotherapy is a generic term used for any anticancer treatment medication.

Epigenetic drugs, or epi-drugs, are approved by the U.S. Food and Drug Administration (FDA) to treat certain cancers. These include ER-positive metastatic breast cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma and multiple myeloma. As well as a precursor to leukemia called myelodysplastic syndrome.

Valproate, DHAC, belinostat, decitabine and vorinostat are epi-drugs that have been studied in clinical trials for mesothelioma.

Epigenetic Research on Mesothelioma

Scientists have been testing epi-drugs that can fight mesothelioma in labs and with real people in trials. If the drug looks like it will work, they try it out on real people to see if it really helps. The following epi-drugs have been evaluated in mesothelioma clinical trials.

Valproate

A 2011 phase II clinical trial tested a combination of two drugs, valproate and doxorubicin, on 45 people with pleural mesothelioma. Seven out of the 45 saw their tumors shrink by half. About 36 percent of the participants responded to the drug, including patients whose tumors stopped growing for a period of time.

Unfortunately, two patients who exhibited poorer overall health died from toxicity caused by the drugs. Researchers determined the drug combination is effective in some patients. But it should only be administered to people with overall good health.

DHAC

In 1997, a phase II clinical trial studied the effect of dihydro-5-azacytidine (DHAC) in 41 people with malignant mesothelioma.

Around 17% of the people taking part in the study had a reaction to the medicine. Two patients saw their tumors shrink by half and one person’s cancer completely disappeared. They didn’t have a recurrence in 6 years of follow-up. Around 20% experienced some heart problems such as an increased heartbeat or fluid around their hearts.

Belinostat

In 2009, a phase II study of belinostat as a singular therapy was studied in 13 people with pleural mesothelioma. The drug halted tumor growth in two participants, but did not shrink tumors or significantly extend survival. The researchers concluded belinostat is not effective on its own, but should be studied in combination with other anti-cancer drugs.

Decitabine

In 2006, a phase I clinical trial evaluated the effect of decitabine in six people with pleural mesothelioma. The drug stopped tumor growth for two mesothelioma patients. Researchers stated the drug proved active against mesothelioma and that further research in combination with other drugs is warranted.

Vorinostat

In 2015, results were published from a phase III clinical trial that studied the effect of vorinostat as a singular therapy in 661 pleural mesothelioma patients whose cancer had recurred following chemotherapy.

Median overall survival among participants receiving vorinostat was approximately 30 weeks compared to 27 weeks among participants receiving a placebo. Researchers concluded vorinostat did not significantly impact survival and do not recommend it as a singular therapy for mesothelioma.

Current and Future Research

In 2015, researchers conducting laboratory tests in mice with mesothelioma discovered epi-drugs targeting EZH2, an enzyme involved in epigenetic changes, were more effective in mesothelioma tumors with the BAP1 mutation. Approximately 50 to 60 percent of mesothelioma tumors carry the BAP1 mutation, which suggests EZH2-targeting epi-drugs may be more effective in this population.

A phase II clinical trial began in 2016 to evaluate the EZH2-targeting epi-drug tazemetostat in pleural mesothelioma patients with and without the BAP1 mutation. The study concluded in 2019, but the results have not been published.

Another clinical trial that started in 2016 is studying a different EZH2-targeting epi-drug called mithramycin in mesothelioma patients. It is still recruiting participants.

A 2021 clinical research study identified UHRF1 as a potential epigenetic target. The study determined asbestos could increase UHRF1 expression which was notably higher in mesothelioma patients. The overexpression of UHRF1 was associated with decreased overall survival in patients. UHRF1 knockout decreased mesothelioma proliferation and invasion.