Modeling Biological Systems
“Advances in high-content imaging technology, multiparametric image analysis, and automation of screening in cell-based models have enhanced our ability to model and understand disease biology at increasingly earlier stages in drug discovery,” says Beverley Isherwood, Ph.D., team leader in the advanced science and technology laboratory at AstraZeneca. The group is applying high-content analysis in complex cell models to assess drug efficacy in single agent and combination drug screens. They are developing co-culture, 3-D, and kinetic models of biological processes to simulate complex biological systems for profiling the mechanism of action (MoA) of experimental compounds.
One example is a human primary co-culture model of angiogenesis that is useful for performing multiplexed assays capable of identifying vascular modulating agents, obtaining MoA information, and predicting cytotoxicity in a high-throughput screen upstream of preclinical testing.
“This model allows us to evaluate not only direct effects on human endothelial and stromal cells, but also effects on autocrine and paracrine signaling between cells,” Dr. Isherwood explains. The company has put in place end-to-end automation of long-term co-culture screens, from cell plating through to data processing.
The researchers are extending these approaches to ex vivo tissue analysis, enabling the incorporation of kinetic information and the study of cells and tissue in co-culture and 3-D environments, “which is allowing us to apply high-content approaches to more complex models of disease biology” for rapid repositioning of drugs and early-stage predictions of the safety and efficacy of a drug or drug combinations, adds Dr. Isherwood.
In the area of oncology, the group is applying high-content screens to generate compound phenotypic fingerprints by assessing compound activity in cells derived from different patient backgrounds to understand how genetics affects response to treatment. They are exploring the ability to apply phenotypic high-content analytical approaches that integrate both kinetic and endpoint measures of phenotype across in vitro and ex vivo clinical samples.
Evidence of a phenotypic effect in vitro that correlates with a similar finding in clinical samples strengthens the predictive potential of the assays and leads to the identification of biomarkers of efficacy.
Dr. Isherwood believes that, in the future, the application of molecular pathway profiling techniques and emerging imaging modalities such as fluorescence lifetime will make it possible to gather even more information from a screen and to identify endpoints that facilitate the translation of phenotypes to in vivo and clinical outcomes.