Epigenetic Therapy.

Abstract

Abstract Epigenetic changes such as alterations in DNA methylation and histone modifications have been well described in various malignancies and are now recognized as targets of therapy (epigenetic therapy). The aim of epigenetic therapy is to reverse epigenetic changes and reactivate important genes thereby modifying the malignant phenotype and inducing clearance of the malignant clone by various mechanisms. Epigenetic modifying agents may also have mechanisms of anticancer action unrelated to gene reactivation. The hypomethylating drugs azacitidine and decitabine induce clinically meaningful remissions or improvements in 30-60% of patients with myeloid leukemias and prolong survival compared to standard approaches including chemotherapy. Both drugs been approved in the USA for the treatment of advanced and/or symptomatic MDS. Their clinical activity in other malignancies including breast cancer is poorly defined because published studies used drug doses and schedules of administration that are not optimal for epigenetic activation. New clinical trials are addressing their potential role in solid tumors. Histone deacetylase inhibitors belong to another class of epigenetic modifying agents. Clinically, they have impressive single agent activity in lymphoid malignancies, but have been disappointing so far in other cancers. However, they are synergistic with many cytotoxic or targeted agents, and their ultimate clinical role may well lay in combination studies. Current studies are focusing on identifying drugs that target additional epigenetic pathways such as the polycomb group proteins, as well as combinations of drugs to affect multiple epigenetic pathways simultaneously. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES4-3.