Epigenetic Pharmacology
Drugs targeting the writers, readers and erasers of epigenetic marks are a rapidly growing class of agents available for mechanistic laboratory studies. Increasingly these agents are being tested in human clinical trials, typically in a cancer setting, and making their way through the Food and Drug Administration (FDA) approval processes. Drugs targeting DNA methylation, such as 5-aza-2'-deoxycytidine (5-azadC), were the first FDA-approved epigenetic drugs that inhibit the DNMT family of DNA methylation writers. Drugs targeting histone acetylation and histone methylation writers, readers and erasers are rapidly emerging and a number of these agents also have been FDA-approved.
Despite rigorous testing and design of epigenetic targeting agents, the mechanisms by which they act to modulate key cell growth regulatory pathways remain unclear. For example, 5-azadC is known to inhibit DNA methyltransferases and in dividing cells lead to demethylation of aberrantly hypermethylated tumor suppressor genes. Reactivation of these growth control genes may contribute to restoration of normal cell cycle or apoptosis checkpoints, but these agents cause DNA damage and induce a DNA double strand break response. It remains unclear how much this latter mechanism contributes to the anti-tumor effects of DNA demethylating agents such as 5-azadC.
In a similar vein, drugs targeting histone mark writers and erasers are typically thought to act through altered histone modifications, chromatin structural changes and subsequent transcriptional responses. Histone writers and erasers, however, also have nonhistone targets and altered post-translational modification of these nonhistone substrates (for example: chaperones and p53) may be major contributors to the anti-tumor activity of these agents.
In the Epigenetic Etiology of Human Disease Laboratory, research in epigenetic pharmacology is focused on:
- Understanding how drugs targeting DNA methylation exert their effects on cell growth, and how they affect downstream cytosine modifications
- Elucidating novel mechanisms for epigenetic drugs
- Identifying new pharmacological vulnerabilities created by mutations in epigenetic regulators like TET2 or SETD2 (also termed synthetic lethality)
The long-term goal of this work is to be able to utilize existing epigenetic drugs and develop new ways to target aberrant epigenetic processes more effectively. This in turn is expected to improve patient responses to these drugs, reduce toxicity and allow for more tailored use of drugs toward the people most likely to respond based on the characteristics of their tumor.