Is epigenetic target therapy a cure for cancer treatment ?
--drug design and cellular mechanism

Yi-Ching Wang, PhD

Department of Pharmacology, College of Medicine, National Cheng Kung University

Cancer is one of the major causes of death over the world. Even with the multi-modality therapies and the recent advent of novel molecularly targeted therapies, the clinical responses to chemotherapy of many cancers is still very unsatisfactory. Thus, to develop more novel affective anti-cancer drugs for lung cancer are urgent needed. It is now realized that CpG island hypermethylation with change in chromatin structure and in histone modifications, collectively resulting in a transcriptional silencing of genes. Overexpression of DNA methyltransferases DNMT1, DNMT3a, and DNMT3b has been reported in various malignancies including hepatomas, prostate, colorectal, breast, and lung tumors. Even though no direct alterations in histone deacetylase (HDAC) genes have been demonstrated in cancer, the association of HDACs with alterations of various oncogenes and tumor suppressor genes is now well established, as is the potential for HDAC involvement in tumorigenesis. The potential reversibility of epigenetic states offers exciting opportunities for novel cancer drugs that can reactivate epigenetically silenced tumor-suppressor genes. Blocking either DNMT or HDAC activity could potentially inhibit or reverse the process of epigenetic silencing. DNMTs and HDACs are the two major drug targets for epigenetic inhibition to date.
Several DNMT inhibitors have exhibited potent antitumor activity in human xenograft models, suggesting their usefulness as novel cancer therapeutic agents. Several are currently in phase I/II clinical trials both in hematological malignancies and in solid tumors. These can be divided into structural classes, including (1) nucleoside DNMT inhibitors and (2) non-nucleoside DNMT inhibitors. Several HDAC inhibitors are currently in phase I/II clinical trials both in hematological malignancies and in solid tumors. These can be divided into structural classes, including (1) carboxylates (short-chain fatty acids), (2) small-molecule hydroxamates, (3) electrophilic ketones (epoxides), (4) cyclic peptides, (5) benzamides, and (6) other hybrid compounds. In this lecture, the drug design and cellular mechanism of these DNMT and HDAC inhibitors will be described. In addition, several novel epigenetic anticancer drugs tested in the lung cancer model of my laboratory will be discussed.