Abstract
Abstract Pancreatic cancer (PC) has 5-year survival rates of 11% and is projected to become the second leading cause of cancer-related deaths by 2030. Poor outcomes result from early metastasis and a lack of effectual therapies for advanced disease. Our previous large-scale genomics studies revealed PC is molecularly highly varied (1). This heterogeneity, lack of effective therapies and high mortality rate make PC a prime arena to advance personalised medicine strategies, where individual cancers are selected for optimal therapy depending on molecular subtype. Utilising our significant experience of molecular-guided anti-cancer therapies (2-6) and stromal biology expertise (2,6,7), we are taking drug-repurposing approaches to test agents with effects on stromal biology in combination with standard-of-care chemotherapies and immunotherapy, to improve clinical outcomes. Itraconazole is an FDA-approved anti-fungal with potential anti-cancer effects, although its efficacy in PC remains relatively unexplored. Preliminary in vivo findings indicate that itraconazole, in combination with standard-of-care chemotherapy gemcitabine/nab-paclitaxel, significantly delays disease progression in both mouse and patient-derived xenograft models of PC. Single cell RNA-seq analyses of tumors from the KPC orthotopic model of PC suggest itraconazole treatment can inhibit immunosuppressive aspects of the stroma and pro-tumorigenic, pro-metastatic signalling. Excitingly, combining itraconazole with anti-PD1/-CTLA4 immunotherapy provides significant survival advantages in the KPC orthotopic model of PC. Finally, using a model of metastatic PC, we show that itraconazole hinders metastatic colonisation in the liver. This work aims to identify subtypes of PC responsive to itraconazole allowing optimisation and translation of tailored therapies combining itraconazole and the latest clinically-utilised chemotherapies and immunotherapies.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
