Epigenetic therapy is a novel treatment that seeks to reactivate the cellular mechanisms that prevent mesothelioma growth.
Table of Contents
Key Points
- Epigenetic therapy works by altering cell expression.
- Although still at an early stage for mesothelioma, it has shown success in other cancers.
- Clinical trials are testing epigenetic therapies alone and in combination with mesothelioma.
- Researchers hope targeting the epigenome could treat and prevent mesothelioma.
What Is Epigenetic Therapy?
Epigenetic therapy, which examines changes in DNA, is a relatively recent treatment connected to gene therapy. Unlike gene therapy, which modifies the sequence of DNA, epigenetic therapy focuses on changes in DNA expression. Epigenetic changes in cells are natural and normal, but can be altered by factors such as age, lifestyle, and toxic exposures. The researchers found that patients with mesothelioma and other cancers have an epigenetic mechanism that disables the cell’s anti-cancer system, thereby allowing tumors to grow. By learning more about the role of epigenetics in cancer.
Epigenetic Changes In Mesothelioma
A 2010 study found a correlation between epigenetic changes and the number of asbestos fibers deposited in the lung tissue of people with pleural mesothelioma. The same study also found a correlation between epigenetic changes and survival in patients with pleural mesothelioma.
A number of epigenetic changes have even helped doctors distinguish between normal pleural tissue and cancerous pleural tissue.
Researchers look for ways to harness these epigenetic modifications to aid in the search for a cure for mesothelioma. A number of clinical trials have been conducted in persons with pleural mesothelioma to evaluate epigenetic medicines, with variable outcomes. A handful of patients responded quite well, with one patient going into remission for more than six years.
How Epigenetic Therapy Works
The primary principle of this therapy is to target epigenetic changes with drugs that reverse the damage and return DNA expression to its pre-cancerous state.
These drugs are designed to detect epigenetic changes associated with cancer, similar to the way chemotherapy targets rapidly dividing cancer cells. Epigenetic cancer drugs are even commonly referred to as chemotherapy drugs, a general term used for any cancer treatment drug.
Epigenetic drugs or drugs are approved by the US Food and Drug Administration (FDA) for the treatment of ER-positive metastatic breast cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma, and a leukemia precursor called myelodysplastic syndrome.
The FDA currently approves five different epigenetic drugs:
- Azacytidine was approved in 2004 for the treatment of the myelodysplastic syndrome.
- Vorinostat was approved in 2006 for the treatment of lymphoma.
- Decitabine was approved in 2006 for the treatment of the myelodysplastic syndrome.
- Romidepsin was also approved in 2009 for the treatment of lymphoma.
- Panobinostat was approved for the treatment of multiple myeloma in 2015. It was also approved for the treatment of peripheral T-cell lymphoma in combination with another epileptic drug called belinostat.
Epi-drugs that have been explored in clinical trials for mesothelioma include valproate, DHAC, belinostat, decitabine, and vorinostat.
Types of Epigenetic Therapies
Histone Deacetylase Inhibitors
- Histones are alkaline proteins that wrap and organise DNA into nucleosomes, allowing gene expression to occur.
- HDAC inhibitors modify histones to allow the DNA to be wrapped more tightly, which leads to the expression of genes associated with a healthy cell cycle and tumor suppression
DNA Methyltransferase Inhibitors
- Methyl is added to DNA (methylate) to affect gene function and expression.
- According to research, the amount of DNA methylation has a major impact on survival (hypermethylation leads to shorter survival)
- DNMT inhibitors interfere with hypermethylation patterns, which can lead to tumor growth and development
Epigenetic research on mesothelioma
Several epi-drugs have been tested against mesothelioma in laboratory conditions and in human clinical trials. Epilepsy drugs that show an anti-cancer effect in the laboratory are further studied in clinical trials. The following epi-drugs have been explored in clinical trials for mesothelioma.
Valproate
In a 2011 phase II clinical trial, valproate was coupled with the chemotherapeutic medication doxorubicin, and the response of 45 patients with pleural mesothelioma was assessed. Seven of the subjects had a partial response, which meant that their tumors shrank by half. Around 36% of participants responded to the treatment, including some whose tumors temporarily stopped growing.
Unfortunately, two patients who showed overall poorer health died of drug toxicity. Researchers have found that the drug combination is effective in some patients, but should only be given to people in overall good health.
AUTUMN
A phase II clinical trial of dihydro-5-azacytidine (DHAC) in 41 individuals with malignant mesothelioma was conducted in 1997.
About 17 percent of participants responded to the drug, including two patients whose tumors shrank in half and one patient whose cancer disappeared completely and did not recur during six years of follow-up. Heart problems — including rapid heartbeat and pericardial effusion — were reported in about one-fifth of the participants.
Whiteness
In 2009, a phase II trial of belinostat as single therapy was conducted in 13 people with pleural mesothelioma. The drug stopped tumor growth in two participants but did not shrink tumors or significantly prolong survival. Belinostat, the researchers found, is ineffective on its own and should be examined in combination with other anticancer medications.
Decitabine
A phase I clinical trial including six persons with pleural mesothelioma was conducted in 2006. The drug stopped tumor growth in two mesothelioma patients. The researchers said the drug has been shown to be effective against mesothelioma and that further research in combination with other drugs is warranted.
Vorinostat
In 2015, the results of phase III clinical trial were published, which studied the effect of vorinostat as a single therapy in 661 patients with pleural mesothelioma whose cancer had recurred after chemotherapy.
The median overall survival for participants taking vorinostat was approximately 30 weeks compared to 27 weeks for participants taking a placebo. The researchers concluded that vorinostat did not significantly affect survival and do not recommend it as a single therapy for mesothelioma.
Current and future research
In 2015, researchers conducting laboratory tests on 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 a BAP1 mutation, suggesting that epi-drugs targeting EZH2 may be more effective in this population.
In 2016, a phase II clinical trial began to evaluate the EZH2-targeting epi-drug tazemetostat in patients with pleural mesothelioma with and without BAP1 mutation. The study was closed in 2019, but the results have not been published.
Another clinical trial, which began in 2016,is studying another EZH2-targeting epi-drug called mithramycin in mesothelioma patients. Participants are still being recruited.
A 2021 clinical research study identified UHRF1 as a potential epigenetic target. The study found that asbestos can increase the expression of UHRF1, which was significantly higher in mesothelioma patients. Overexpression of UHRF1 was associated with reduced overall patient survival. UHRF1 knockout reduced mesothelioma proliferation and invasion.
Risks and Benefits of Epigenetic Therapy
While clinical trials to date have shown mixed results for mesothelioma, researchers remain hopeful because epigenetic treatments have been demonstrated. proven success for other health conditions. Although the treatment’s effectiveness in prolonging survival can vary greatly by the patient, researchers have noted that overall, it is a safe treatment that can work. best as a second-line cancer treatment for recurrent mesothelioma.
So far in clinical trials, researchers have noted that epigenetic therapy is generally less toxic than standard treatments such as chemotherapy and has fewer side effects. Many of the risks associated with epigenetic therapy can also be reduced with lifestyle or dietary changes.
Risks of Epigenetic Therapy
- Nausea
- Vomiting
- Fatigue
- Constipation
- Decrease in the number of white blood cells
- Difficulty breathing (dyspnea)
Several mesothelioma clinical trials incorporating epigenetic treatment are presently underway. The researchers expect that further research will lead to this cancer medication being an effective first-line treatment.
Clinical Trials Trial of Epigenetic Therapy for Mesothelioma
Researchers have tested multiple drugs that target HDAC or DNMT to treat pleural mesothelioma, with mixed results. Many of these clinical trials are still in the early stages, focusing on understanding the combination of epigenetic therapies with other treatments to improve efficacy. Several epigenetic drugs, sometimes labeled as chemotherapy drugs, are approved by the FDA to treat solid tumors, cancer, and other health conditions.
Because epigenetic medications are commonly referred to as chemotherapy drugs, numerous clinical trials have combined these novel treatments with chemotherapy. One study treated 45 patients with pleural mesothelioma with the HDAC inhibitor valproate (also known as valproic acid) and the chemotherapy drug doxorubicin. Patients receive one to six cycles of therapy, with varying degrees of success. Median progression-free survival was only 2.5 months, with only 25% of patients surviving a year or longer. Overall, however, the researchers note that the treatment is safe and may be an effective regimen for patients with recurrent pleural mesothelioma.
Vorinostat, another epigenetic medication, was utilized in a comparable phase III research of individuals with recurrent pleural mesothelioma who had previously received chemotherapy. The researchers concluded that the drug was not effective, as survival was extended to about 31 weeks compared with 27 with the standard of care.
Despite some of these experiments yielding dismal results, researchers are continuing to investigate the impacts of epigenetic regulation and potential multimodal methods. Various studies show that epigenetic therapy combined with immunotherapy can lead to improved outcomes and an extended lifespan.