PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks have significantly higher incidence rates of PDAC and decreased survival times compared to Whites and Latino/Hispanics (L/H) even after socioeconomic status and tumor stages are controlled. Therefore, it is likely different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The molecular characteristics that distinguish PDAC tumors between racial groups have the potential to identify novel therapeutic targets required to overcome the disparities. Indeed, delineating the underlying molecular basis for health disparities in lung, breast and prostate cancers has led to therapeutic advancements and improved patient outcomes. Similar breakthroughs for PDAC are possible and needed for this deadly disease, but this field of research has not yet been adequately explored. We identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative mass spectrometry data. These PDAC subtypes are predictive of therapeutic response, but this has not yet been analyzed in a racially diverse population. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks, L/H, and Whites. In PDAC tumors from Black patients, we observed features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflammatory microenvironment and resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. Therefore, strategies are needed to modulate subtype to improve response to chemotherapy. Toward this goal, our proteomic analysis also identified that the polycomb repressor complex 1 protein RNF2 is upregulated in PDACs from Blacks compared to Whites. We have also discovered that RNF2 regulates mRNA expression of the PDAC subtype specification factor GATA6 and inhibiting RNF2 promotes a molecular shift toward the more chemosensitive Classical subtype of PDAC. In general terms, the Specific Aims in this proposal are designed to: 1) Determine the interaction between race and PDAC subtype development in PDX models; 2) Determine the impact of RNF2 on EZH2 regulation of GATA6 and in diverse PDAC PDX models; and 3) To quantify the response of PDAC PDX to select NCI-IND compounds targeting epigenetic modifiers. The successful completion of these aims has the potential to mitigate racial health disparities in PDAC and broadly improve overall patient survival by optimizing precision therapeutic strategies.