Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Abstract

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

“…Recent studies highlight disruption of epigenetic regulators as potential therapeutic targets . In bladder cancer, KDM6A loss causes the upregulated levels of H3K27me3, and then can be used as a surrogate marker for the treatment of EZH2 inhibitors .…”

“…Clinical trials of HDAC inhibitors have shown beneficial effects on part of hematological malignancy and solid tumor entities. Three HDAC inhibitors, vorinostat, panobinostat and romidepsin, have reached approval by the FDA for the treatment of cutaneous T‐cell lymphoma and multiple myeloma . In contrast to hematopoietic cancers, the disappointing results of HDAC inhibitor monotherapy in solid tumors including PDAC lead to clinical trials evaluating combination therapy.…”

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

“…Whole-genome sequencing studies have identified inactivating mutations of chromatin modifiers as frequent genetic events in PDA tumors (Waddell et al, 2015). In addition, small-molecules that target readers, writers, or erasers of histone modifications have shown promising therapeutic effects in mouse models of PDA by altering transcription of cancer genes (Hessmann et al, 2017). A recent study has shown that disruption of large heterochromatin domains is associated with the metastatic transition in PDA, as a consequence of aberrant oxidative pentose phosphate metabolism (McDonald et al, 2017).…”

Chromatin remodelling controls pancreatic tissue fate

“…Significant improvement of PDAC prognosis is hampered by restricted therapy response of PDAC patients which is—on the molecular level—primarily caused by an extreme intertumoral heterogeneity 1. Besides the core genetic alterations (oncogenic mutation of KRAS , inactivation of the core tumour suppressors TP53, CDKN2A and DPC4 ) PDAC is characterised by a plethora of additional molecular events that, although occurring less frequently, are of prognostic and predictive significance 2 3.…”

“…For instance, approximately one-third of PDAC tumours carry mutations in genes coding for chromatin regulatory proteins 2. Epigenetic alterations installed by changes of the chromatin landscape critically impact on tissue homeoestasis and can foster malignant transformation and tumour progression 1. This is particularly true for the SWI/SNF (SWItch/sucrose non-fermentable) complex of chromatin remodelling proteins, which physiologically disrupts the tight contact between DNA and histones and mobilises nucleosomes to reveal previously hidden genes to the transcription machinery 4.…”