Repurposing itraconazole as a novel and promising therapeutic strategy for pancreatic cancer

Pancreatic cancer has the highest mortality rate among all main cancer types and is the 3rd leading cause of cancer death in Australia. Standard chemotherapy for advanced pancreatic cancer only imparts a modest clinical benefit as the overall 5-year survival of all stages of the disease remains only at 10-12%. While research into novel treatments is urgently required, the balance between continued innovation and the monetary expense needs to be considered, as the costs of new drug development have been increasingly shifted to patients which can negatively affect clinical outcomes and quality of life. Repurposing drugs offers a rational, evidence-based approach which can provide sustainable access to cost-effective therapeutic options for cancer. Accordingly, this thesis has examined repurposing itraconazole, which is an inexpensive and well-tolerated oral antifungal agent currently in use clinically as a novel treatment for pancreatic cancer. We utilised a combination of in vitro and advanced in vivo techniques and models (including mouse models of aggressive pancreatic cancer and well-annotated patient-derived cell-lines), 16S RNA sequencing of the gut microbiome and single cell transcriptomics to systemically examine itraconazole’s efficacy and potential mechanisms of action in pancreatic cancer. This thesis demonstrates the potential direct anti-tumour effects of itraconazole, predominantly in in vitro settings, coupled with significant modulatory effects on the tumour microenvironment in vivo. Itraconazole reduced proliferation and invasion of pancreatic tumours, lessened metastatic colonisation, induced cell cycle quiescence in cancer cells of metastatic sites and modulated angiogenesis. Itraconazole further augmented the efficacy of standard cytotoxic chemotherapy to significantly improve overall survival in immunocompetent and patient-derived mouse models of pancreatic cancer, compared to chemotherapy alone. Of note, itraconazole positively improved the “immune-cold” tumour milieu of pancreatic cancer by affecting macrophage polarisation, T cell heterogeneity, chemokine signalling, inducing transcriptional changes in immune cell populations and altering gut microbiome signatures. Ultimately, the addition of itraconazole to immunotherapy significantly inhibited tumour progression and improved survival in a mouse model of pancreatic cancer, compared to immunotherapy alone. Our findings demonstrate the potential for the repurposing of itraconazole in combination with chemotherapy and immunotherapy for the treatment of pancreatic cancer.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2023

Author dc:creator

• Man, Jennifer

• Repurposing itraconazole
• therapeutic strategy
• pancreatic cancer

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/25277

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/101570