Discussion

The emergence of novel targets such as epigenetic modulators shows considerable promise but remain poorly understood from a clinical perspective. The ability to test new agents, alone or in combination, in predictive human models would support the identification, optimization and development of compounds for the clinic. Human primary cell-based BioMAP Systems are designed to recapitulate the complex signals and phenotypic responses of diseased tissues and thus provide broad biological coverage of inflammation, wound healing, tissue remodeling, vascular and epithelial biology. We have recently expanded the platform to include oncology systems employing co-cultures of primary human fibroblasts or endothelial cells with PBMCs and a cancer cell line. Profiling in BioMAP enables better understanding of the human pharmacological and toxicological properties of compounds, including on- and off-target effects, dose responses, discrimination of closely related compounds and indication selection. This proven predictive approach provides an unsupervised, structure-independent measure of overall phenotypic impact of compounds under disease-like conditions and identifies clinically relevant activities across a broad protein biomarker panel. Profiling compounds for new targets, such as BET family epigenetic readers, revealed target-specific phenotypic signatures that confirm mechanism of action. In addition BET inhibitor activities in the Oncology systems showed efficacy related anti-inflammatory effects, matrix-remodeling activities and reduced expression of a tumor-restricted marker. BioMAP Systems thus provide a highly useful platform to (1) identify anti-inflammatory and anti-cancer effects of various target inhibitors and (2) identify different phenotypic outcomes of these agents that influence cancer progression and disease resolution. Together these BioMAP data will support the discovery and development of safer and more effective therapies in cancer and other diseases.