Targeting the epigenome of pancreatic cancer for therapy: challenges and opportunities

In 2018, there was an estimated 55,440 new cases of pancreatic adenocarcinoma (PDAC) in the United States. Generally, most new cases are in an advanced stage, usually due to the lack of symptoms during the early stages of the disease. Currently, the vast majority of therapeutic regimens have shown only modest effects in this setting, and median survival ranges from 6 to 11 months. Indeed, better therapies for these patients are urgently needed. Epigenetics refers to the somatically heritable differences in gene expression not attributable to intrinsic alterations in the primary sequence of DNA. Core elements of the epigenetic regulation of gene expression include how DNA is packaged around nucleosomes, how chromatin and nucleosomes are modified by a complex series of enzymes and their subsequent interactions with proteins that recognize these modifications. The recognition of the essential role of epigenetic alterations in the development and progression of PDAC has revolutionized our knowledge of this disease and has immediate translational implications for targeting epigenetic abnormalities in PDAC for therapeutic purposes. Moreover, recent work with epigenetic modulatory drugs (EMDs) has shown that these agents may be capable of altering the immunogenicity of the tumor microenvironment (TME), to reverse immune suppression and to ‘prime’ tumors for immunotherapy. This review summarizes the current knowledge of epigenetic alterations in PDAC with a focus on the translational application of targeting epigenetic-based events as new therapeutic approach for this disease.