| dc.description.abstract | As we expand our understanding of the complex entanglement between genetic and epigenetic abnormalities that shape the malignant cancer phenotype, epigenetic therapies gain more and more clinical relevance. Pioneering these pursuits is the first generation of DNA methyltransferase (DNMT) inhibitors (DNMTi), which incite global cellular DNA hypomethylation. This elevates tumour immunogenicity by the restoring antigen processing machinery, re-establishing cancer antigen expression, enhancing cytotoxic T cell tumour infiltration and inducing viral mimicry. The resultant anti-tumour response proved effective in eliminating certain myeloid malignancies, with DNMTis receiving FDA-approval for the treatment of multiple leukaemic disorders. However, their application in lymphomas and solid tumours demonstrated disappointing results, paralleling the outcomes obtained with other well-established epigenetic therapies. Because of this, the research focus has largely shifted from monotherapies to combinatorial approaches incorporating alternative oncotherapies. Preclinical research revealed that DNMTi-induced genome-wide demethylation can reverse chemoresistance and T cell exhaustion, thereby sensitizing refractory tumours to chemotherapeutic and immunotherapeutic interventions. They were also shown to synergize with other epigenetic therapies e.g. histone deacetylases (HDAC), lysine-specific histone demethylase 1A (LSD1) and enhancer of zeste homolog 2 (EZH2) inhibitors, greatly reducing tumour growth and progression in mouse models. The potency of combination treatments is evident in in vivo models, however translation into the clinic has yielded mixed results. Despite this, they wield immense potential that will require a great deal of clinical testing to be fully realized, although the application of powerful auxiliary technologies like nanoparticle-based drug delivery and CRISPR/Cas9 may accelerate this process. | |
