Abstract 6576: Exploring the role of circulating extracellular vesicles in chemotherapy resistance and cachexia in advanced pancreatic cancer

Abstract Advanced-stage pancreatic (ductal adenocarcinoma) cancer (APC) is an incurable malignancy with an average survival of less than a year. Although combination chemotherapy (FOLFIRINOX, gemcitabine/nab-paclitaxel, liposomal irinotecan-based) regimens offer improved survival compared with single agent gemcitabine, chemotherapy resistance (CR) and cancer cachexia (CC) are universal phenomena near the end of life. CC is an inflammatory process marked by anorexia and weight loss, muscle wasting (sarcopenia), fat depletion (adipopenia) and profound fatigue. CR leads to the uncontrolled growth of tumor cells that accelerates CC. Both processes are thought to be reflected in and in part mediated by circulating extracellular vesicles (EVs), which contain molecular cargo from their tissues of origin. Given the lack of tumor biopsies performed during the treatment course of APC, we analyzed circulating EVs from a patient-derived, serially collected blood biobank to identify proteins that could serve as potential biomarkers of and therapeutic targets for both CR and CC. In this study, we isolated EVs from nine patients with double- and triple-chemotherapy refractory APC from our Pancreatic Cancer Biobank. Proteomic and phospho-proteomic analyses via mass spectrometry were conducted and differential protein expressions were compared across 3 timepoints: 1. Pre-treatment; 2. Remission; and 3. Chemotherapy resistance towards the end of life. These were also compared against healthy matched controls (n=5). Our analysis identified 269 differential proteins, with 61 unique to late relapse and 66 unique to pre-treatment, indicating their associations with CR and CC. At late-relapse, 16 proteins were downregulated and 16 were upregulated (log2FC>1, p<0.05). Top downregulated proteins included RAPGEF1, PPP1CA, LUZP2, PIGG, and NAMPT, while the most upregulated proteins were WNT9B, GFAP, POLK, ADGRB3, and MYH8. Several of these proteins are associated with the Wnt signaling pathway, known to influence cachexia. Phosphoproteomic analysis identified 15 uniquely phosphorylated proteins at relapse, including BRD7 and UBR2, also implicated in Wnt signaling. This is the first study to longitudinally track proteomic changes in circulating EVs from stage IV, chemotherapy-refractory PC patients, providing a unique perspective on CR and CC. Ongoing validation of these results in additional patient samples, coupled with in-vitro studies exploring the functional and mechanistic roles of these proteins in CR and CC offer the potential to disrupt pancreatic cancer progression and its devastating consequence of cancer cachexia. Citation Format: Shatovisha Dey, Tammy Lo, Alpana Dholakia, Julianna Cuateco, Sabina Swierczek, Richard C. Frank. Exploring the role of circulating extracellular vesicles in chemotherapy resistance and cachexia in advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6576.