Esophageal cancer (EC) is a devastating disease with limited therapeutic options and a pressing need for improved treatments. A current major gap is the lack of therapies that target molecularly defined subsets of EC, limiting the current treatment to traditional chemotherapy, radiation, and surgery. However, recent research from the Shilatifard lab has identified a druggable vulnerability in the de novo nucleotide synthesis pathway in cancer cells lacking a functional MLL3/4-COMPASS complex. Mutations in two components of the complex, MLL4 and UTX, occur in approximately 25% of EC cases and may present a unique opportunity for targeted intervention. This project will explore whether MLL4 and UTX mutations similarly sensitize EC cells to the FDA-approved drug pemetrexed, which targets three enzymes in the de novo nucleotide synthesis pathway.
The study will evaluate MLL4 and UTX mutations as determinants of pemetrexed response in EC and characterize the functional and molecular consequences of these mutations on tumor biology. Using EC cell lines and xenograft models, the researchers will assess the anti-tumor efficacy of pemetrexed in MLL4/UTX-mutant EC samples and identify robust gene expression signatures associated with treatment response. The ASPIRE award aims to establish preclinical evidence for stratifying EC patients by mutation status in clinical trials and advancing personalized treatment strategies. By leveraging molecular genetic advances, this project seeks to repurpose an existing oncology drug for tailored therapy in a significant subset of EC patients.