Abstract

Mechanism-Based Therapeutic Targeting Of Epigenetic Abnormalities In Solid Tumours: Clinical Update And Future Directions

Sophie Postel-Vinay, Group Leader, Institut Gustave Roussy

The past three years have seen, for the first time in solid tumors, promising therapeutic successes with to the use of epigenetic modifiers. Chromatin remodeling defects, which occur in at least 20% of solid tumors, can be selectively targeted using mechanism-based approaches such as synthetic lethality or epigenetic antagonism. An illustration of such strategy is the inhibition of EZH2 in SMARCB1- and SMARCA4-deficient tumors. The recent pre-clinical description of several genetic dependencies between genes coding for subunits of chromatin-remodeling complexes calls for clinical evaluation. Regarding oncogene addiction, most successes have been obtained with the use of BRD4 inhibitors in Nut-midline carcinomas, but the clinical proof-of-concept remains to be done in Myc-driven tumors or castration-resistant prostate cancer. Several lines of preclinical evidence also support that epigenetic modifiers could serve as immunomodulatory agents, either by modulating the tumor cells characteristics, the immune cells lineage or function, or by shaping the tumor microenvironment. Key data in this field will be summarized in this presentation.