Epigenetics is a relatively new, exciting area of life sciences that has enormous implications for new drug therapeutics. Epigenetics encompasses tumor suppressor genes that halt abnormal cell growth and how they can become ineffective without being mutated.
Epigenetics involves cellular mechanisms, similar to colored highlighters used to distinguish different parts of text with different meanings. There are a variety of epigenetic marks layered on top of DNA sequences, which tell the cell’s proteins to process the DNA differently. There are certain genetic markers that act like flags to attract proteins specifically designed to shut down the area in the cell that is flagged.
These epigenetic “flags” can change depending on the needs of the cell. For example, there are different patterns of epigenetic methyl groups during a baby’s development versus adulthood. Epigenetics, then, refers to the study of long-term changes in gene expression not caused by changes to the DNA sequence.
Epigenetics and Cancer
Flawed epigenetic flags or DNA methylation patterns are hallmark characteristics of cancer cells. Many cancer types, including mesothelioma, may develop because of flaws in the epigenetic environment. These flaws can cause several harmful changes, such as silencing tumor-suppressing genes and activating proto-oncogenes, both of which lead to cancer growth. In other words, cancer likely can turn certain genes on or off, allowing tumorous tissue to go undetected by the body’s natural immune defense.
Epigenetic modification has a very wide influence on cell regulation, inhibiting genes that are involved in DNA repair, apoptosis (programmed cell death), cell cycle regulation, drug resistance, differentiation, metastasis and angiogenesis (blood vessel growth).
There are several mechanisms by which epigenetic regulation takes place. In cancer cells, DNA is both hypermethylated (tagged with excessive methyl groups) and hypomethylated (tagged with fewer than normal). Hypermethylation causes the silencing, or inactivation of tumor suppressor genes, which then prevents the normal functioning that keeps tumor cell growth in check. In lung cancer samples, more than 80 genes are hypermethylated. On the other hand, hypomethylation causes active transcription, leading to the classic uncontrolled growth of tumor cells.
Fortunately, epigenetic changes are often dynamic and reversible, and so they are good targets for cancer therapy. Epigenetic therapy offers a potential means of influencing flawed gene environments directly.
Using a variety of pharmaceutical drugs in epigenetic therapy, a gene expression profile which is pathogenic is transformed into a gene expression profile which is associated with normal tissue. In other words, certain drugs can block the silencing of tumor-suppressing genes and provide an opportunity to reset the DNA to its pre-cancer state.
There are a variety of epigenetic therapies for some cancer types that have shown promise in clinical trials, and which may be used singularly or in conjunction with other therapies.
Two enzymes that are important in epigenetic modifications are also key targets for therapy with pharmaceutical drugs. These are called histone deactylases (HDACs), which modify histones, and DNA methyltransferases (DNMTs), which methylate DNA. There have been successful clinical studies carried out for both.
Epigenetic therapy has proven successful for several types of cancer, including lung cancer, breast cancer, and lymphoma.
Epigenetic Therapy For Mesothelioma
Belinostat, an epigenetic therapy used successfully for lymphoma, is in early phase development for treatment of mesothelioma. The drug has gone through Phase I clinical trials to determine how the body responds to the drug, feasibility, and tolerability, and high doses were tolerated. The optimal dose and schedule, however, need to be determined with additional clinical trials.
In the most promising clinical trial to date, the epigenetic therapy valproic acid in combination with chemotherapy treatment was tested in a Phase II study of 45 mesothelioma patients. It was effective in patients who had good performance status (80-100) with recurrent, refractory or metastatic mesothelioma after chemotherapy. However, further study is needed to validate the effectiveness of this combined therapy.
Benefits of Epigenetic Therapy
Epigenetic therapy, a relatively new therapy, has shown great promise in effectiveness against hematological malignancies (tumors that affect the blood, bone marrow, lymph, and lymphatic system) and solid tumors, gaining FDA approval for cutaneous T-cell lymphoma, ER-positive metastatic breast cancer, myelodysplastic syndrome, multiple myeloma, and peripheral T-cell lymphoma. Pharmaceutical drugs which target the epigenomes of mesothelioma patients have shown promise in early clinical trials when used singularly or in combination with current therapies.
FDA Approved Epigenetic Therapy and Chemotherapy Drugs
The chemotherapy drug classified as an epigenetic therapy, Vorinostat, is sold as Zolinza® by Merck. Vorinostat works through growth arrest or apoptosis of cancer cells and was FDA approved in 2006 for treatment of lymphoma in patients with recurrent, progressive or persistent disease after previous treatment with two chemotherapies. Phase II studies have shown efficacy of Vorinostat combined with tamoxifen for breast cancer treatment. The two therapies in combination are well tolerated.
Another chemotherapeutic epigenetic therapy, Romidepsin (Istodax®), was approved by the FDA in 2009, also for treatment of lymphoma.
The chemotherapy drug Azacytidine, which targets epigenetic changes by inhibiting methylation in high-risk myelodysplastic syndrome (MDS) was effective in treating 60% of patients in a Phase III randomized controlled trial and was FDA approved in 2004 for treatment of myelodysplastic syndrome.
The chemotherapy drug Decitabine, another DNA methylation inhibitor, was FDA approved in 2006 also for treatment of myelodysplastic syndrome.
The epigenetic therapy panobinostat, in combination with dexamethasone and the chemotherapy drug bortezomib was FDA approved in 2015 for treatment of multiple myeloma. Another 2015 FDA approval was made for the treatment of peripheral T-cell lymphoma with the epigenetic therapy, belinostat.