Researchers have known for many years that inheritable phenotype changes can occur that do not involve changes in DNA sequences. This type of inheritable difference is referred to as an epigenetic change, and differs from genetic changes that result from nucleic acid base alterations in the DNA sequences of genes. The term “epigenetics” was first used by Conrad Waddington in the 1940s, even before the structure of DNA was understood, but it has taken a few decades of research aided by advances in instrumentation and software to appreciate the epigenetic control mechanism. Today, we know that epigenetics has an important role in embryonic development and is also involved in aging and disease processes such as cancer.
Genetic information resides on chromosomes that consist of chromatin, the combination of DNA and histone protein, and other proteins. The functions of chromatin are to package DNA so it fits inside the cell nucleus, to strengthen the DNA for the rigors of cell division, and to control DNA replication and gene expression. I’m focusing here on the epigenetic control over gene expression by changes in chromatin structure, affected by chemical modifications of histone proteins and direct methylation of DNA.
The first mechanism of epigenetics to be widely studied was DNA methylation. DNA methylation is a chemical modification in which a methyl group is added to the cytosine group in the DNA. DNA methylation patterns in normal and cancer cells differ making the DNA methylation mechanism an attractive drug target, since increased DNA demethylation appears to be useful in the treatment of cancer. Two of the four FDA-approved epigenetic drugs are demethylating agents, and most of the diagnostic activity to date in epigenetics has focused on methylation markers.
A second epigenetic control mechanism involving the modification of histones has been discovered. Histones are small, alkaline proteins that are associated with DNA. Segments of DNA wrap around the histones to form nucleosomes, the basic structural unit of chromatin, which resembles a “string of beads,” the string being the DNA and the histones, the beads. The extent of condensation of chromatin varies during the stages of the cell lifecycle. For example, in non-dividing cells, most of the chromatin is relaxed and not tightly condensed. However, in situations where the chromatin is highly condensed, genes cannot be transcribed thus resulting in a gene transcription control mechanism. The N-terminal domain of histones is modified by various enzymes to modulate the degree of condensation. These modifications can include enzyme catalyzed chemistries such as acetylation, methylation, or phosphorylation. These modifications may either activate or repress transcription of the genes. Among the histone modifying enzymes, histone deacetylases (HDACs) and histone methyltransferases represent targets for drug development.
The first epigenetic drugs to reach the market target hematological cancers. Within the hematological market, the currently approved indications for these epigenetic drugs represent fairly small markets. The two DNA hypomethylation agents [Celgene’s Vidaza (azacitidine) and Eisai’s Dacogen (decitabine)] are both FDA-approved for treatment of myelodysplastic syndromes (MDS), while the two FDA-approved HDAC inhibitors [Merck’s Zolinza (vorinostat) and Celgene’s Istodax (romidepsin)] are indicated for treatment of cutaneous T-cell lymphoma (CTCL). It is expected that epigenetic drugs may prove to be useful for treatment of a wide range of diseases including hematological cancers, solid tumors, and other non-cancer indications.
Al Doig is general manager, Insight Pharma Reports. He can be reached at firstname.lastname@example.org.