Abstract A020: Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer

Abstract Pancreatic adenocarcinoma (PDAC) remains one of the fatal cancers due to its poor prognosis and the lack of effective treatments, often diagnosed at advanced stages. There is an urgent need for innovative and selective therapies as current treatments show limited efficacy and significant side effects. Our proteomics analysis of extracellular vesicles from PDAC tumor cells revealed a distinctive imbalance in secreted amino acids. Specifically, we found that PDAC cells preferentially excrete proteins enriched with amino acids such as isoleucine and histidine, which are linked to disease progression. By targeting these exocytosed amino acids, we observed selective toxicity against PDAC cells in both in vitro and in vivo experiments. Additionally, we identified XRN1 as a potential target influenced by these amino acids. This approach demonstrated high selectivity, targeting tumor metabolism with minimal toxicity to normal tissues, and showed to be easy to administer with sustained tumor-killing effects. Our findings suggest that targeting exocytosed amino acids offers a promising therapeutic strategy for PDAC and potentially other cancers. Citation Format: Alfred Akinlalu, Zachariah Flaten, Komila Rasuleva, Ang Guo, Sijo Mathew, Dali Sun. Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A020.