Abstract A029: Re-purposing non-oncology agent itraconazole to target the dynamic cellular ecosystem of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of only 10% and persists as the third most common cause of cancer-related death in Western societies. Precision medicine is a likely future for all cancer treatment, but may have its greatest impact in less common, high-mortality and molecularly heterogeneous cancers, including pancreatic cancer. Fortunately, in the era of Big Data, bioinformatic analyses of genomic datasets have helped us gain new insights of how novel molecular-guided therapies can modulate signalling within tumors and their ecosystem (Vennin et al. 2017; Waddell, N, Pajic, M, Patch, AM. et al. 2015; Chou A. et al. 2018; Lau, MT. et al 2020). In this study, we delineate, at single-cell resolution, the complex stromal mechanisms by which a clinically-used, orally available anti-fungal agent itraconazole improves the overall anti-tumor response in PDAC. Single-cell RNAseq analysis of the genetically-engineered KPC model (LSL- KrasG12D;LSL-Trp53 R172H/+) revealed significant downregulation of the pro-tumorigenic CD105+ cancer-associated fibroblast (CAF) signature post-itraconazole therapy in vivo. Moreover, single-cell trajectory inference of CAFs subsets revealed a marked effect of treatment on myofibroblasts (myCAFs), which produce the fibrotic PDAC desmoplasia. In support of these findings, immunofluorescence analyses further demonstrated decreased deposition of collagen and altered matrix remodelling within itraconazole-treated tumors. Within the antigen-presenting apCAF and inflammatory iCAF populations, itraconazole treatment led to decreased pro-tumorigenic Igf1-Itga6:Itgb4 signalling to specific tumor cell subsets, which was functionally associated with reduced metastatic colonisation in vivo. apCAFs also showed decreased expression of H2-Aa and CD74, major antigens expressed by apCAFs which act as decoys for corresponding receptors on CD4+/CD8+ T cells, thus leading to their impaired activation (Lakins et al, 2018). These potentially promising effects on the immune environment of PDAC were supported by significant positive changes within macrophage populations, including enrichment of M1-like pro-inflammatory macrophage signatures (confirmed via immunofluorescence), and further associated with positive signalling via Cxcl9-Cxcr3 and Tnf1rs-1a/1b ligand-receptors. scRNAseq revealed dampening of regulatory T cell homing and functional potency signals within the pancreatic tumor microenvironment was associated with increased CD8+ T-cell infiltration post-itraconazole treatment, and importantly, significantly improved response to immune checkpoint blockade in an advanced in vivo model of pancreatic cancer. In summary, these integrated bioinformatic and molecular studies provide scientific rationale for the development of itraconazole and immunotherapy combination in pancreatic cancer. Citation Format: Diego Chacon-Fajardo, Sean Porazinski, Jennifer Man, Howard Yim, Emad El-Omar, Anthony Joshua, Marina Pajic. Re-purposing non-oncology agent itraconazole to target the dynamic cellular ecosystem of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A029.