Until recently, scientists thought genetic mutations played a bigger role in cancer risk than epigenetic changes to our DNA. However, it has become widely accepted that epigenetics potentially plays an equal if not bigger role in cancer than genetic mutations.
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, while epigenetic changes do not alter our DNA, but rather the expression of our DNA.
Epigenetic change is a normal and natural process, but it is affected by age, environment, lifestyle, disease state and toxic exposure. For example, asbestos exposure contributes to epigenetic changes, but scientists aren’t precisely sure how yet.
Epigenetic Changes in Mesothelioma
A 2010 study found a correlation between epigenetic changes and the amount of asbestos fibers embedded in the lung tissue of people with pleural mesothelioma. The same study also found a correlation between epigenetic changes and survival among pleural mesothelioma patients.
The number of epigenetic changes even helped doctors distinguish normal pleural tissue from cancerous pleural 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.
How Epigenetic Therapy Works
The primary principle behind this therapy is targeting epigenetic changes with drugs that reverse damage and return the expression of DNA back to its pre-cancerous condition.
These drugs are designed to sniff out epigenetic alterations related to cancer, which is similar to the way chemotherapy targets rapidly dividing cancer cells. Epigenetic cancer drugs are even commonly referred to as chemotherapy drugs, which 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 ER-positive metastatic breast cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma and a type of leukemia called myelodysplastic syndrome.
Five different epigenetic drugs are currently approved by the FDA:
- Azacytidine was approved in 2004 to treat myelodysplastic syndrome.
- Vorinostat was approved in 2006 to treat lymphoma.
- Decitabine was approved in 2006 to treat myelodysplastic syndrome.
- Romidepsin was approved in 2009 to also treat lymphoma.
- Panobinostat was approved in 2015 to treat multiple myeloma. It was also approved to treat peripheral T-cell lymphoma when combined with another epi-drug called belinostat.
Valproate, DHAC, belinostat, decitabine and vorinostat are epi-drugs that have been studied in clinical trials for mesothelioma.
Epigenetic Research on Mesothelioma
Several epi-drugs have been tested against mesothelioma in laboratory settings and in human clinical trials. Epi-drugs that show an anti-cancer effect in the lab go on to be studied in clinical trials. The following epi-drugs have been evaluated in mesothelioma clinical trials.
A 2011 phase II clinical trial combined valproate with the chemotherapy drug doxorubicin and evaluated the response in 45 pleural mesothelioma patients. Seven participants had a partial response, meaning their tumors shrunk in 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 should only be administered to people with overall good health.
In 1997, a phase II clinical trial studied the effect of dihydro-5-azacytidine (DHAC) in 41 people with malignant mesothelioma.
Approximately 17 percent of participants responded to the drug, including two patients whose tumors shrunk in half and one patient whose cancer completely disappeared and had not recurred during six years of follow-up appointments. Heart problems — including fast heartbeat and pericardial effusion — were reported in approximately one-fifth of participants.
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.
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.
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 is no longer recruiting participants and is expected to wrap up in late 2018.
Two other clinical trials, one that began in 2012 and another that started in 2016, are studying a different EZH2-targeting epi-drug called mithramycin in mesothelioma patients. Both are still accepting participants.
Share this article
Last Modified December 19, 2018
9 Cited Article Sources
McLoughlin, K., Kaufman, A., and Schrump, D. (2017, June). Targeting the epigenome in malignant pleural mesothelioma.
Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504118/
John Hopkins Medicine. (n.d.). What is epigenetics?
Retrieved from: https://www.hopkinsmedicine.org/kimmel_cancer_center/research_clinical_trials/research/su2c/what_is_epigenetics.html
NOVA. (2007, October 16). Epigenetic therapy.
Retrieved from: http://www.pbs.org/wgbh/nova/body/epigenetic-therapy.html
Furlow, B. (2015, November 3). Mesothelioma BAP1 mutations might represent a promising target for epigenetic therapy.
Retrieved from: http://www.oncotherapynetwork.com/lung-cancer-targets/mesothelioma-bap1-mutations-might-represent-promising-target-epigenetic-therapy
Grisham, J. (2015, October 23). Collaborative research suggests targeting BAP1 may help treat mesothelioma.
Retrieved from: https://www.mskcc.org/blog/collaborative-research-suggests-targeting-bap1-may-help-treat-mesothelioma
Scherpereel, A. et al. (2011). Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study.
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/20530048
Krug, L. et al. (2015, April). Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/25800891
Ramalingam, S. et al. (2009, January). Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma.
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/19096314
- Yogelzang, N. et al. (1997, June). Dihydro-5-azacytidine in malignant mesothelioma. A phase II trial demonstrating activity accompanied by cardiac toxicity. Cancer and Leukemia Group B. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/9179072/