Predicting response to epigenetic therapy

Abstract

Drugs targeting the epigenome are new promising cancer treatment modalities; however, not all patients receive the same benefit from these drugs. In contrast to conventional chemotherapy, responses may take several months after the initiation of treatment to occur. Accordingly, identification of good pretreatment predictors of response is of great value. Many clinical parameters and molecular targets have been tested in preclinical and clinical studies with varying results, leaving room for optimization. Here we provide an overview of markers that may predict the efficacy of FDA- and EMA-approved epigenetic drugs.

Figure 1. Mechanism of action DNMTis.

(A) Under normal circumstances, the DNMTs copy the methylation pattern of the parental DNA strand after replication, ensuring that methylation patterns are maintained during cell division. (B) During treatment, DNMTis are incorporated into DNA and RNA, where they covalently bind and thus inactivate DNMTs. After successive cell divisions, the original DNA methylation pattern is lost.

Figure 2. Cellular pathways affected by DNMTis and HDACis.

DNA methylation and acetylation of histone and proteins play important roles in multiple cellular pathways, which may be affected by DNMTis and HDACis. Accordingly, the inhibition of HDACs or DNMTs can lead to miscellaneous responses, each of which may require a different biomarker.