Abstract 6414: Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer

Exosomes play a critical role in promoting proliferation and survival of cancer cells. These extracellular vesicles that range in size from 30-100nm in diameter are released by many different cell types and contain proteins, nucleic acids, and micro RNAs that can modify the content and state of recipient cells. Our previous studies have shown that cancer-associated fibroblasts (CAFs), which make up the bulk of pancreatic ductal adenocarcinoma (PDAC) tumors, hypersecrete exosomes upon chemotherapy treatment. When these exosomes were taken up by surrounding cancer cells, we observed more cell proliferation and drug resistance. Considering these findings, there is clearly a need of therapeutic strategies that target exosome biogenesis and secretion. Here, we investigate the effectiveness of several compounds, including farnesyl transferase inhibitors, imidazoles, and nonsteroidal anti-inflammatory drugs (NSAIDs), in blocking exosome secretion and suppressing chemoresistance in PDAC CAF and cancer cell lines. We observed decrease in exosome secretion upon ketoconazole, tipifarnib, and neticonazole treatment, using GW4869 (a neutral sphingomyelinase inhibitor) as our control. Furthermore, we established a 3D organoid model from our PDAC mouse models to better understand the impact of these drugs on exosome secretion in tumors with different genetic alterations. Together, our 2D and 3D models illuminate the potential for pharmacological targeting of exosome secretion as a treatment option that can improve the current standard-of-care treatment in PDAC. Citation Format: Chae Young Eun, Charlene DeKalb, Weikun Xiao, Xinyu Zhang, Reginald Hill. Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6414.