Poster Presentation 30th Lorne Cancer Conference 2018

Itraconazole as a novel treatment for pancreatic cancer (#161)

Jennifer Man 1 , Danielle Froio 1 , Rhys Stark 1 , Ashleigh Parkin 1 , Alison Drury 1 , Nicolas Vogel 1 , Angela Steinmann 1 , Stacey Walters 2 , Adnan Nagrial 3 , Shane Grey 2 , Paul Timpson 1 , Marina Pajic 1
  1. The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Transplantation Immunology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Crown Princess Mary Centre, Westmead Hospital, Sydney, NSW, Australia

Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies with an overall 5-year survival rate of 8%. Despite significant recent efforts into developing novel therapeutics, gemcitabine and nab-paclitaxel chemotherapy remains the standard-of-care for patients with advanced PC, despite imparting only a marginal overall survival advantage of 1.8 months. Extensive molecular heterogeneity of PC, few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. Itraconazole is an inexpensive, safe, orally administered and clinically used anti-fungal agent, recently shown to possess anti-cancer activities in a range of malignancies including lung, prostate and ovarian cancer (Aftab et al. 2011; Antonarakis et al. 2013). Despite the lack of preclinical studies of itraconazole in PC, there are several remarkable case-reports and retrospective studies suggesting significant efficacy (Tsubamoto et al. 2015; Lockhart et al. 2015). Here we aim to explore the potential therapeutic benefit of itraconazole and rationally-designed combination therapies in vitro and in vivo utilising our robust and well-characterised patient-derived xenograft (PDX) and cell line (PDCL) models of PC. In vitro, PDCLs exhibited a diverse range of sensitivities to itraconazole, and sensitive lines (IC50<5µM) displayed strong synergism when treated with itraconazole in combination with gemcitabine chemotherapy. Data also suggest a correlation of itraconazole sensitivity with NPC1 receptor expression in our PDCLs, which may warrant further investigation of NPC1 as a potential biomarker of response (Head et al. 2015). In vivo, combination of itraconazole and chemotherapy significantly reduced tumour burden and improved overall survival in a KPC mouse model of PC. Our findings demonstrate the potential efficacy of repurposing itraconazole as a cheap and safe complement to chemotherapy in PC, a molecularly varied disease in dire need of tailored and effective treatment strategies.

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