Caroline Green

New Favorite in the Pharmaceutical World: Epigenetic Drugs

Blog Post created by Caroline Green on Jan 7, 2020

Epigenetics was proposed in the 1950s by Conrad Waddington, a British developmental biologist, to describe the interaction between genes and the environment during development, thereby regulating and determining the ultimate fate of tissues and organs. Epigenetics focuses on heritable changes in gene expression without changes in the nucleotide sequence of the gene.

Epigenetics and Cancer

Mutations in genes encoding epigenetic regulators are common in tumors, and the consequences are mainly reflected in four aspects: DNA promoter hypermethylation, extensive DNA hypomethylation, altered histone modifications and abnormal chromatin structure. Promoter hypermethylation causes repression of tumor suppressor gene transcription. However, the instability of the genome, resulting from extensive hypomethylation of DNA, may lead to aberrant activation of oncogenes. Mutations in histone modifying enzymes in tumors, including histone methylases, demethylases, acetylases, etc., can also cause abnormal gene expression and thus determine the tumor cell phenotype. All these epigenetic changes can affect tumor cell growth, immune escape, metastasis, heterogeneity, and drug resistance, and even some of them may directly contribute to tumorigenesis.

What are the epigenetic drugs?

Researchers interested in the combined use of epigenetic therapy and immunotherapy currently focus on two major classes of epigenetic drugs.

The first class is histone deacetylase (HDAC) inhibitors. These drugs act on the histones that wrap the DNA by controlling how tightly the DNA is wrapped around the histones. Histone deacetylases, through the deacetylation of histones (removal of acetyl groups), wrap DNA more tightly around histones, thus making these DNAs less accessible to gene transcription factors. As a result, the expression of proteins involved in cell differentiation, cell cycle arrest, tumor immunity, and apoptosis of damaged cells was inhibited. These factors all contribute to the development of cancer.

A second class of epigenetic drugs are DNA methylation inhibitors (DNMTi). These drugs prevent cancer cells from genetically adding methyl groups. DNA methylation can silence genes that delay cell division and thus contribute to uncontrolled cell proliferation. There are two kinds of DNMTi, a nucleotide analogue, which bind to DNA to form a covalent complex, and the complex will promote the degradation of DNMT. Azacitidine and decitabine are DNMTi and have been used in more than 200 leukemia and solid tumor-related clinical trials and are currently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndrome.

Difficulties faced by epigenetic drugs in clinical application

Specificity is one of the greatest difficulties limiting the use of epigenetic drugs for the clinical treatment of cancer. First, the mutated epigenetic factor does not simply modify a gene, a segment of DNA, histones, and chromatin, and the result may be one-to-one or one-to-many. Second, there are also problems with the use of drugs, such as DNMTi, which has a wide range of effects and is not specific. When DNMTi is used to reactivate repressed tumor suppressor genes, there is also a risk of high expression of oncogenes. In addition, mutations are constantly changing in different histiocytic tumors, during periods of tumor progression. Whether individual factors have an impact on epigenetic efficacy requires further investigation. How to solve the high dose dependence and improve the efficacy is also a difficulty that needs to be broken.

Although there are still many problems that are difficult to solve, epigenetic therapy shows certain new advantages over traditional drug therapy. Epigenetic alteration plays an important role in tumor immunity. The expression of tumor antigen is reduced due to the promoter hypermethylation of antigen gene, and antigen presenting cell (APC) cannot recognize it, which results in immune escape. Epigenetic drugs such as DNMTi have been shown in early clinical trials to be effective in stimulating the expression of histocompatibility complexes and enhancing tumor killing by effector T cells. Therefore, the combination of epigenetic drugs can improve the efficacy of immunotherapy. On the other hand, the drug resistance of traditional anticancer drugs in the treatment of cancer has been a difficult problem. Epigenetic drugs can inhibit the development of drug resistance and enhance drug efficacy. At the same time, epigenetic drugs can directly act on cancer cells that have developed drug resistance and inhibit or kill cells. It is believed that more epigenetic drugs will be approved for marketing in the next few years, and such emerging drugs are bound to inject new vitality into cancer therapy.