Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of only 10% and persists as the 3rd most common cause of cancer-related death in Western societies. New treatment options are urgently needed. We have previously defined specific molecular subgroups of PDA associated with pre-clinical and clinical response to select tailored treatment strategies. One such interesting molecular-guided therapy involves repurposing non-oncology agent, anti-fungal itraconazole, to target distinct elements of tumour - stroma signalling in pancreatic cancer.
Our data indicate that itraconazole can effectively modify pancreatic tumour architecture to improve the efficacy of latest, clinically-used therapeutic combinations in PDAC. In a genetic model of advanced, metastatic pancreatic cancer, itraconazole hindered metastatic colonisation in the liver, significantly delayed disease progression, while modulating stromal biology and inhibiting immunosuppressive elements. Single-cell RNA sequencing analyses further revealed alterations in the signalling within distinct tumour-associated macrophage populations, alongside decreased pro-tumourigenic, pro-metastatic signalling within cancer cell and cancer-associated fibroblast populations post-itraconazole therapy. For instance, expression of H2-Aa and CD74, major antigens expressed by pro-metastatic CAFs that act as decoys for corresponding receptors on CD4/CD8 T cells leading to their impaired activation, was significantly reduced post-itraconazole, effect accompanied by improved CD8+ T cell infiltration in treated PDAC tumours.
Our findings indicate that therapeutic efficacy of FDA-approved anti-fungal itraconazole may be the result of targeting both tumour cells and key aspects of the PDAC microenvironment. Collectively, these data provide scientific rationale for the design of tailored itraconazole plus standard-of-care chemotherapy combinations as well as new ways of improving the overall anti-tumour immunity in pancreatic cancer.