Pilot Project 5

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ABSTRACT – Pilot Project 5 Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and the survival rate remains stagnant with a 5-year survival rate of only 5-8%. Black/African Americans (B/AA) individuals experience the highest prevalence and lowest overall survival rates of PDAC compared to their White counterparts. FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) is often the preferred chemotherapy treatment choice for patients with PDAC, but considerable toxicities have limited its use. The decreased expression of nucleoside transporters due to genetic and epigenetic reasons appeared to account for Gem resistance. In addition, deoxycytidine kinase (dCK), which is responsible for Gem phosphorylation into the active form, is postulated to correlate with Gem efficacy. To address these challenges, we have modified Gem to 4-(N)- stearoylGem (4NSG) to: i) block the CDA attack on Gem, and ii) increase Gem transport into PDAC cells. Our recent results revealed highly expressed epidermal growth factor receptors (EGFR) in pancreatic tumor samples. Guided by our recently published and unpublished results, we hypothesize that optimized 4NSG nanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy of Gem. We propose the following specific aims to address this hypothesis. Aim 1: Test the efficacy of 4NSGnpcetu, in B/AA, and White patient-derived organoid models (PDOs) with stroma and in primary PDAC cells. Aim 2: Evaluate the therapeutic efficacy of 4NSGnpcetu in PDAC PDX mouse models bearing subcutaneous tumors from B/AA and White patients. Aim 3: Measure dCK RNA/protein expression in PDAC PDX tumor models and SNP genotypes in PDAC cases and controls in the MultiEthnic dataset. Our studies will determine whether racial differences in dCK variant, gene expression, and protein activity can correlate with improved Gem efficacy in B/AA and /or White PDAC patients. The valuable information obtained will significantly advance the overall goal of improving the response and survival rate in PDAC patients.