Poster Presentation 35th Lorne Cancer Conference 2023

From functional genomics to precision medicine: targeting the dynamic cellular ecosystem of pancreatic cancer using clinically-safe agents (#301)

Sean Porazinski 1 2 , Jennifer Man 1 , Diego Chacon Fajardo 1 , Howard Yim 3 , Emad El-Omar 3 , Anthony Joshua 2 , Marina Pajic 1 2
  1. Personalised Cancer Therapeutics Lab, Precision Cancer Medicine Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  3. Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, 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. 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 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 therapies2-6 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.

 

Itraconazole is an FDA-approved anti-fungal with potential anti-cancer effects, although its efficacy in PC remains relatively unexplored. Itraconazole can perturb AKT/mTOR signalling – atypically activated in ~25% of pancreatic cancers (ICGC/APGI cohort). Initial data from select patient-derived models demonstrates itraconazole efficacy is correlated with higher AKT levels. Preliminary in vivo findings indicate that itraconazole, in combination with gemcitabine/Abraxane, significantly delays disease progression in a personalised patient-derived xenograft setting. Single cell RNA-seq analyses of tumours from the KPC orthotopic model of PC suggest itraconazole treatment can inhibit immunosuppressive components of the stroma and pro-tumourigenic, pro-metastatic signalling. Excitingly, using a model of metastatic PC, we show 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.

  1. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).
  2. Chou, A. et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut 67, 2142–2155 (2018).
  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).
  4. Belali, T. et al. WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1863, 194642 (2020).
  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).
  7. Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Science Translational Medicine 9, eaai8504 (2017).