New epigenetic drug targets

FO01-03

The progressive acquisition of genomic alterations is a defining feature of all human cancers: cancer cells are known to carry a variety of genetic defects, including gene mutations, deletions, translocations, and amplifications, that endow the cells with new capabilities for dysregulated proliferation, inappropriate survival, tissue invasion and destruction, immune system evasion, and metastasis. More recently, it has become apparent that cancer cells also carry epigenetic defects, including changes in cytosine methylation patterns and in chromatin structure and organization, which are equivalent to genetic changes in effecting and maintaining neoplastic and malignant phenotypes. For many human cancers, evidence has accumulated to suggest that somatic epigenetic alterations may appear earlier during cancer development than genetic changes, as well as more commonly and consistently. As a consequence, the study of somatic epigenetic changes has provided new insights into the mechanism(s) of carcinogenesis, new molecular biomarkers to aid in prostate cancer detection and diagnosis, and new opportunities for prostate cancer prevention and treatment. One epigenetic change, CpG island hypermethylation, leads to the epigenetic silencing of critical genes by recruiting 5-methyl-CpG-binding domain (MBD) family proteins capable of mediating transcriptional repression via effects on chromatin structure. As part of an effort to discovery and develop small molecule drugs targeting MBD repression pathways for the therapeutic reactivation of epigenetically silenced genes in prostate cancer cells, “high-throughput” chemical screening has yielded a number of lead compounds capable of activating transcription from hypermethylated GSTP1 promoters, a gene epigenetically silenced in nearly all prostate cancers, and most breast and liver cancers. Several compounds identified in this way were found to directly interfere with transcriptional trans-repression mediated by MBDs via antagonizing the binding of MBDs to methyl-CpG-containing DNA. These MBD antagonists reactivated epigenetically silenced genes in cancer cells, and synergistically increased silenced gene expression the presence of DNA methyltransferase inhibitors.