Abstract

Application of Super-enhancer Analysis for Drug Discovery

Christian Fritz, Vice President, Syros

Super-enhancers (SEs) are large, highly active chromatin regions that drive key genes important for cell identity and cell fate. In immune cells, SEs are associated with genes that respond to inflammatory signals and in cancer cells SEs are often associated with oncogenes and non-oncogene drivers of the tumor cell state. We are exploiting these observations to gain fundamental insights into disease and to identify novel drug targets and drugs linked to patient populations. In cancer, we have mapped genome-wide SEs in more than 50 primary tissue samples from AML and breast cancer patients. In breast cancer, SE analysis recapitulates known clinically validated targets and subgroups (ER+, Her2+, TNBC) and reveals new targets that are selectively associated with SEs in specific subtypes of breast cancer. We can also use SEs to cluster patients into subgroups. In AML, we show that these novel patient groups are not distinguished by mutations but correlate with overall survival. We are validating novel targets implicated by SE association in patient samples in two different ways: 1) by using shRNA and CRISPR knock down in cell line models and 2) through the use of existing small molecules through our Enhancer Drug Gene Evaluation (EDGE) platform. We are particularly interested in gene control targets, and we will give examples of both biological and chemical validation of such targets. By starting in patient tissue and validating in cancer cells with an SE as a biomarker, we are starting with a patient selection hypothesis designed to enable precision medicine. Our chemical validation through EDGE is especially suited for acceleration of compounds into the clinic, and we will give an example of a compound that we are advancing into a Phase 2 clinical study in genomically defined AML and MDS patients based on our SE maps. We are now expanding this approach beyond breast cancer and AML into other areas, including additional cancers, immuno-oncology and inflammatory disease