Epigenetic Therapies in Solid Tumours: From Preclinical Models to Clinical Trial Results

Abstract

All types of cancer show widespread aberrant epigenetic changes, leading to changes in expression of genes involved in all the classic hallmarks of cancer, as well as genes involved in how tumours will respond to chemotherapy. These epigenetic changes can be, at least temporarily, reversed using small molecule inhibitors of maintenance of the epigenetic state. Demethylating agents and histone deacetylase inhibitors have shown activity against certain haematological malignancies; however, their activity in solid tumours remains more uncertain. For successful treatment of solid tumours with epigenetic therapies, major challenges remain in the delivery of epigenetic therapy, the maintenance of a pharmacodynamic response and the achievement of a therapeutic index. In addition, the development of robust predictive biomarkers linked to an understanding of the underlying biology will be key to improved epigenetic therapy approaches. Defining the epigenetic profile of individual cancer subtypes may allow epigenetic therapy to be targeted to those groups of patients who are most likely to benefit from this treatment. Furthermore, targeting drug-resistant or tumour-sustaining subpopulations of tumour cells with epigenetic therapies may be vital, especially given the key role of epigenetic mechanisms in maintenance of a stem cell state. Finally, an overview of published clinical trials with epigenetic drugs (alone or in combination with other epi-drugs, differentiation-inducing agents, tyrosine kinase inhibitors or chemotherapy) is given for different solid tumour entities. These results clearly demonstrate that this approach has successfully entered the clinical arena. Examples include the encouraging results of hypomethylating agents in combination with carboplatin in platinum-refractory ovarian cancer and combination studies in non-small cell lung cancer.