Yuan Gao, PhD

During postdoctoral training with Dr. Vakoc at the Cold Spring Harbor Laboratory, Gao discovered that the ETS family transcriptional repressor ETV6 is a unique dependency in Ewing sarcoma, which is a highly aggressive bone cancer that affects children and young adults. She identified a detailed mechanism underlying how targeting of ETV6 converts EWS-FLI1 from an oncoprotein into a tumor suppressor by reprogramming its genomic occupancy. Notably, ETV6 is largely dispensable for homeostasis in the majority of mammalian tissues, making this TF an attractive target for this pediatric tumor. However, transcription factors, like ETV6, are considered 'undruggable' targets due to a lack of suitable small-molecule pockets. To challenge this notion, Gao profiled metabolites that can bind ETV6 to uncover its endogenous chemical ligands. These efforts were inspired by the nuclear hormone receptor protein family, where knowledge of metabolite binding sites has allowed for effective pharmacological strategies. Using a biochemical screening strategy, she discovered a specific interaction between phosphatidic acid and ETV6. Further characterizations indicate that this ligand binds to the SAM domain of ETV6 and regulates its oligomerization. Since ETV6 oligomerization is critical to support Ewing sarcoma, Gao intends to deepen the biochemical and genetic evaluation of this ETV6 ligand with the long-term goal of leveraging these insights to develop tool compounds and drugs that modulate this TF. Going forward, her laboratory will combine innovative genetic screening methodologies with biochemical and structural tools to advance targeted therapies in Ewing sarcoma, and ultimately other cancers. A key hypothesis underlying her research is that transcriptional and epigenetic machineries are allosterically regulated by yet-to-be-discovered endogenous metabolites. Elucidation of such mechanisms will reveal fundamental regulatory mechanisms and can potentially provide opportunities to develop novel pharmacology.