Poster Presentation 35th Lorne Cancer Conference 2023

Re-purposing Non-oncology Agent Itraconazole To Target The Dynamic Cellular Ecosystem Of Pancreatic Cancer (#118)

Diego Chacon-Fajardo 1 , Sean Porazinski 1 , Jennifer Man 1 , Howard Yim 2 , Emad El-Omar 2 , Anthony Joshua 3 , Marina Pajic 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Microbiome Research Centre, St George and Sutherland Clinical School, UNSW , Sydney, NSW, Australia
  3. Oncology Department, St Vincent’s Private Hospital, Sydney, NSW, Australia

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 (PC). 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 tumours and their  ecosystem. In this study, we demonstrate at single-cell resolution how a clinically-used, orally available anti-fungal agent itraconazole can effectively modify the transcriptome landscapes of pancreatic tumours and improve the overall anti-tumour response.

A bioinformatic approach applied to murine single-cell RNAseq datasets from genetically-engineered KPC models (LSL- Kras G12 D ; LSL-Trp53 R172H/+) supports promising in vivo findings whereby itraconazole hinders metastatic colonisation in the liver and significantly delays disease progression of advanced PC. Specifically, single-cell trajectory inference of cancer-associated fibroblast (CAF) subsets revealed a marked effect of treatment on myofibroblasts (myCAFs), which produce the fibrotic PDAC environment. These alterations were further associated with decreased deposition of collagen within treated tumours, suggesting lowered myCAF activity. Moreover, reduced expression of H2-Aa and CD74 (apCAF markers) was found in itraconazole-treated tumours. Both genes represent major antigens expressed by apCAFs and act as decoys for corresponding receptors on CD4+/CD8+ T cells, thus leading to their impaired activation (Lakins MA Nature Comms 2018). On the other hand, cell-to-cell communication analysis revealed disruption of selected protumourigenic, pro-metastatic signalling, including the Hedgehog pathway, which plays an important role in tumour angiogenesis, growth and immunosuppression.

In summary, these bioinformatic and molecular studies suggest that itraconazole has positive effects on the pancreatic tumour microenvironment and could pave the way for improving immunotherapy regimens in PDAC.