HUMAN HEALTH
Emily Gordon, PhD working on cancer tumor sensitivity
informed treatment decisions. In addition to their work in pancreatic cancer, the lab is also using a sim- ilar CRISPR screening approach to study resistance mechanisms in ovarian cancer. Led by senior scientist Emily Gordon, PhD, the group aims to predict tumor sensitivity to drugs in combinations often seen in the treatment of ovarian cancer by screening 2,400 genes using the CRISPR activation/knock out system. The results of these experiments will be used to interpret gene expression data gathered from patient tumors pre- and post-treatment and better understand and predict treatment response. Overall, the Cooper lab is dedicated to the iden- tification of novel therapeutic targets, and strategies for treating pancreatic and ovarian cancer, both of which have some of the worst outcomes among cancer patients. Embracing the collaborative spirit of HudsonAlpha, Cooper entered into a joint project with resident company CFD Research. The company has the tools and expertise necessary to solve protein structures and predict drugs that might bind them. Using the three-dimensional structure of the protein, CFD Research can predict which existing chemical compounds might be able to attach to it and render it non-functional. In their collaboration, CFD Research has worked to identify novel inhibitors of the gene ANGPTL4 , a target identified by Cooper and Myers (see page 14 for Myers Lab studies) in 2016. If resis- tance-inducing proteins can safely be turned off using a drug, it could increase the efficacy and success of traditional cancer therapies. n
Cooper’s lab also identified gene pathways as- sociated with drug resistance based on their CRISPR screens. Activation of chromatin remodeling path- ways was one of the most consistent mechanisms of drug resistance identified in the screens. Chromatin remodeling is the dynamic modification of tightly wound DNA, called chromatin, from its condensed, or closed, state to an open state that allows access to the machinery necessary to turn genes on. Widespread closed chromatin has been previously associated with poor prognosis in pancreatic cancer patients. Coo- per’s lab explored the role of one protein involved in chromatin remodeling that is also associated with pa- tient prognosis. Histone deacetylase 1 (HDAC1) is an enzyme that cooperates with chromatin repressors. Overexpressing HDAC1 in cell lines regulated genes that are part of the epithelial-to-mesenchymal tran- sition, a pathway known to be involved in multi-drug resistance. These data further the understanding of the role of HDAC1 and chromatin remodeling in drug resistance and provides important information in the pursuit of improving treatment options for pancreatic cancer. PhD candidate Carter Wright is continuing to pursue the additional work aimed at identifying some of the key genes and pathways downstream of HDAC1 activation that might represent novel therapeutic targets themselves. The data generated through the CRISPR screen completed in Cooper’s lab provides a promising new tool to predict a patient’s likelihood of developing re- sistance to common treatments, and help make
2019-20 Research Report 17
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