Genetic and epigenetic events together establish pro-tumorigenic expression changes that drive a variety of cellular phenotypes observed in this disease. Based on transcriptomic signatures, colorectal cancer patients can be divided into 4 CMS (Consensus Molecular Subtypes) groups that are typified by activation of specific signaling pathways and oncogenic pathways. We have limited understanding of functional contribution of major epigenomic regulatory processes in driving these molecular and cellular phenotypes associated with colorectal cancers. Our preliminary results the heterogeneity of enhancer gains between different patients and identified 4 subgroups of patients based on their speci...

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Genetic and epigenetic events together establish pro-tumorigenic expression changes that drive a variety of cellular phenotypes observed in this disease. Based on transcriptomic signatures, colorectal cancer patients can be divided into 4 CMS (Consensus Molecular Subtypes) groups that are typified by activation of specific signaling pathways and oncogenic pathways. We have limited understanding of functional contribution of major epigenomic regulatory processes in driving these molecular and cellular phenotypes associated with colorectal cancers. Our preliminary results the heterogeneity of enhancer gains between different patients and identified 4 subgroups of patients based on their specific enhancer patterns, labeled as EPIC1 through EPIC4. Interestingly, these EPIC clusters correlated well with expression clusters CMS1 through CMS4. These observations provide rationale to examine functionality of enhancer elements, detailed molecular mechanisms of their establishment and development of personalized therapeutic strategy. We hypothesize that aberrant enhancer activation, a key epigenomic feature of colorectal cancer, drives its progression by regulating important oncogenic pathways in a context dependent manner. We propose that use of bromodomain inhibitors with those CMS-specific pathway inhibitors could prove to be a useful therapeutic strategy. First, we aim to identify functional enhancer elements, their gene targets and downstream mechanism in specific epigenetic subtypes (EPIC). Second, we will determine the driver molecules for specific epigenetic subtypes (EPIC). Third, we will determine the efficacy of BRD inhibition alone or in combination with pathway inhibitors for specific CMS subtypes. The proposed project will identify functional enhancer elements, explore the mechanisms behind their establishment and assess the potential of enhancer blocking agents for combination therapy in specific subgroups of colorectal cancer patients.

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