Targeting cancers by de-repressing nuclear PDC

Epigenetic modifications play a significant role in cancer and its treatment. Targeting metabolic regulators like IDH and chromatin modifiers such as EZH2 is now a clinical option. Sarcomas make up 15-20% of childhood cancers, but treatment choices are limited. Through a combination of small molecule screening and a genome-wide CRISPR activation screen, we identified a specific target as a protein that is nucleus-restricted and inhibits the nuclear-localized pyruvate dehydrogenase complex (nPDC). Pharmacological inhibition of the target raises nuclear acetyl-CoA and alters cell state in cancer cells, potentiated when combined with HDAC inhibitors. In vitro, the result is cell cycle arrest and reversal of epithelial-mesenchymal transition.  In sarcomas in vivo, these changes correlated with reduced tumor growth and tumor-initiating cells in patient xenograft models. By leveraging a tool inhibitor, we aim to understand its mechanism, test analogs for structure-activity relationships, and design new compounds for stronger inhibition. Our goal is to develop lead compounds targeting nuclear organelle-specific acetyl-CoA metabolism as potential therapies for sarcomas.