In-person Oral Presentation 34th Lorne Cancer Conference 2022

From functional genomics to precision medicine: targeting the dynamic cellular ecosystem of pancreatic cancer using clinically-safe agents  (#20)

Sean Porazinski 1 2 , Jennifer Man 2 , Anthony Joshua 1 2 , Paul Timpson 1 2 , Marina Pajic 1 2
  1. St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  2. Personalised Cancer Therapeutics Lab, Precision Cancer Medicine Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Pancreatic cancer (PC) has 5-year survival rates of 10% 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, with 5-year survival rates in metastatic disease just 3%. Our previous large-scale genomics studies revealed PC is molecularly highly varied1. This heterogeneity, lack of effective therapies and high mortality rate make PC a prime model to advance personalised medicine strategies, where individual cancers are selected for optimal therapy depending on their molecular subtype. Utilising our significant experience of molecular-guided anti-cancer therapies2–5 and stromal biology expertise2,6,7, we are taking drug-repurposing approaches to test agents with effects on stromal biology in combination with standard-of-care chemotherapies, to improve clinical outcomes in PC.

Itraconazole is an FDA-approved antifungal with potential anti-cancer effects, although its efficacy in the context of PC remains relatively unexplored. Itraconazole can perturb AKT/mTOR signalling – which is atypically activated in ~25% of pancreatic cancers. Initial data from select patient-derived models demonstrates that itraconazole efficacy is correlated with higher AKT levels in vitro. Preliminary in vivo findings indicate that itraconazole, in combination with gemcitabine/Abraxane, significantly delays disease progression in a personalised patient-derived xenograft setting. Early single cell RNA seq analyses of tumours from the aggressive KPC orthotopic model of PC suggest itraconazole treatment can inhibit immunosuppressive components of the stroma and pro-tumourigenic, pro-metastatic signalling within cancer cells. Excitingly, using a model of metastatic PC we show that itraconazole hinders metastatic colonisation in the liver. This work will aim to identify the subtypes of PC responsive to itraconazole allowing optimisation of tailored combination therapies consisting of itraconazole plus the latest clinically-utilised chemotherapies.

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  3. Li, L. et al. Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer. Br. J. Cancer (2020).
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  5. Uzor, S. et al. CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer. Sci Rep 11, 7963 (2021).
  6. Porazinski, S. et al. YAP is essential for tissue tension to ensure vertebrate 3D body shape. Nature 521, 217–221 (2015).
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