Harnessing epigenetic inhibitors: A promising approach for overcoming challenges in pancreatic ductal adenocarcinoma treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and often fatal form of malignancy frequently diagnosed at an advanced stage, posing significant challenges for treatment. The complex and intricate microenvironment of PDAC, characterized by heterogenous tumoral cells harbouring diverse mutations and epigenetic alterations, immune cells (primarily in an immunosuppressive state), cancer-associated fibroblasts (CAFs), low vascularization and extracellular matrix components supporting tumor growth, creates a physical barrier that impedes drug delivery and anti-tumoral immune cell responses, leading to therapy resistance. Despite advancements in early detection methods, and available treatments for PDAC-including surgery, radiotherapy, chemotherapy, and immunotherapy, all have shown limited efficacy. Recently, liposomal drugs in combination therapy, PDAC-targeted CAR-T cells and anti-tumor RNA vaccines have emerged as promising therapeutic approaches. However, significant challenges remain, including the presence of a dense stroma, resistance to chemotherapy, and robust immune suppression, all of which pose substantial barriers to effective treatments. In this context, epigenetic therapy aims to modify gene expression patterns in PDAC cells, potentially curtailing their resistance. This review provides an overview of the current landscape of PDAC research and the role of epigenetic inhibitors in the treatment of this lethal disease, emphasizing the potential of combining these novel drugs with conventional chemotherapy or immunotherapy, new drug delivery approaches and future directions in the field. A multi-approach therapy, switch to simultaneously targeting various facets of the PDAC characteristics, could enhance the anti-tumoral efficacy by overcoming its resistance mechanisms, improving patient prognosis.

Keywords: Deacetylases; Demethylases; Epigenetic enzymes; Immunotherapy; Methyltransferases; PDAC; Solid tumor.