Discovery
The Grohar lab uses a variety of unbiased screening approaches to identify active compounds and combinations both in our lab and in collaboration with other investigators and biotechnology companies. These studies involve FDA approved compounds as well as novel compounds. More recently, we have focused on the identification of molecular targets that perturb the activity of EWS-FLI1 as a means to better understand the biology of target inhibition and to identify new agents.
Novel Compounds, Analogs and Targets
Compound Screening: Our initial efforts at compound screening were completed in collaboration with the NCI-Frederick. In this effort, we screened more than 50,000 compounds and identified mithramycin as an inhibitor of the EWS-FLI1 transcription factor.
We subsequently screened a series of analogs of mithramycin to identify both a more potent and less toxic second-generation analog, EC8105 and EC8042.
Additional cell line screens suggested that a tumor called Rhabdoid Tumor was particularly sensitive to this class of compounds. We characterized the mechanism of hypersensitivity of rhabdoid tumor and demonstrated inhibition of the defining molecular lesion of the tumor, the SWI/SNF chromatin remodeling complex. Importantly, SWI/SNF has been identified by other groups as the complex associated with EWS-FLI1. Therefore, heightened activity in these two cell types may be related to this activity.
Genetic Screens: Our original efforts with genetic screens were in collaboration with groups at the National Cancer Institute. We identified RNA processing as a therapeutic vulnerability in subsets of Ewing sarcoma tumors. We now have the ability to perform genome-wide screens in our lab and collaborate with investigators at the University of Pennsylvania High-Throughput Screening Core.
Matrix Drug Screens: We believe that improving outcomes in high-risk Ewing sarcoma will likely require combination therapies. One approach to identify these combinations is to use matrix drug screening. We have used this approach to identify the combination of mithramycin and CDK9 inhibitors that may both improve activity and limit the toxicity of mithramycin.
Future directions, goals and current projects: We have ongoing projects and unpublished data in all of these discovery areas. We continue to use screening approaches and novel chemical probes to delineate mechanisms of chemotherapeutic efficacy in Ewing sarcoma and related tumors