Combinations of epigenetic therapy drugs may improve treatment of lung cancer

Stephen Baylin, who is a professor of oncology and medicine from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and his team recently found that combinations of epigenetic therapy drugs potentiated anti-tumor responses in human cancer cell lines as well as in mouse models of cancer.

The full paper (Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer) can be read in the journal Cell.

Professor Baylin's main research interests focus on epigenetics, the study of heritable changes in gene function that do not involve changes in the DNA sequence. His research is aimed to solve a series of questions such as how epigenetic variations contribute to cancer development. In the current study, Professor Baylin and colleagues tested the hyperthesis that combining DNA methyltransferase (DNMT) inhibitors with histone deacetylase (HDAC) inhibitors holds promise for enhancing cancer immune therapy.

DNMTs and HDACs are two families of enzymes that both play key roles in epigenetic regulation of gene expression. DNMTs, HDACs, and the molecular activities modulated by them have been implicated in tumor development. Thus, DNMTs and HDACs are interesting therapeutic targets for cancer treatment. Scientists have been developing DNMT inhibitors and HDAC inhibitors, and some of these epigenetic therapy drugs have shown efficacy in clinics.

Professor Baylin's team examined the effect of a DNMT inhibitor called 5-azacytidine and three HDAC inhibitors known as entinostat, mocetinostat and givinostat in non-small-cell lung cancer (NSCLC). Using NSCLC cell lines, they found that 5-azacytidine suppressed MYC signaling, and adding the HDAC inhibitors further depleted MYC. The Myc signaling pathway plays a key role in various cellular activities such as proliferation, differentiation, transformation and apoptosis. Abnormalities in Myc signaling have been seen in many different types of cancer. The combination of DNMT inhibitor and HDAC inhibitor appeared to suppress cancer cell proliferation.

The team also tested the combination of DNMT inhibitor and HDAC inhibitor in mouse models of NSCLC. This combination treatment modulated T cell phenotypes, potentiated anti-tumor responses, and reversed tumor immune evasion.

NSCLC takes up about 85% to 90% of all lung cancers. Lung cancer is one of the most common cancers in humans and one of the most common causes of cancer death worldwide. Outcomes of patients are strongly associated with the clinical stages of their cancer. Although several types of treatments are available to treat lung cancer, patients with advanced lung cancer have fewer treatment options and worse prognosis.

The promising results of this study emphasized the need to test the combinations of epigenetic therapy drugs in clinical trials. According to Professor Baylin, a large proportion of patients with lung cancer failed to respond to immune checkpoint therapy. Combinations of epigenetic therapy drugs may improve the treatment of these patients.
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