E-Poster Presentation 33rd Lorne Cancer Conference 2021

Fit for repurpose: itraconazole as a novel treatment approach for pancreatic cancer (#142)

Sean Porazinski 1 , Jennifer Man 1 , Paul Timpson 1 , Emad El-Omar 2 , Anthony Joshua 1 , Marina Pajic 1
  1. Personalised Cancer Therapeutics Lab, Precision Cancer Medicine Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Microbiome Research Centre, UNSW, Sydney, NSW, Australia

Pancreatic cancer (PC) has an overall 5-year survival rate of <9% and is projected to become the second leading cause of all cancer-related deaths by 2030. Poor outcomes are due to the majority of cases being diagnosed when PC has already metastasised 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 varied [1-3]. 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 in the development of molecular-guided anti-cancer therapies [4-10] and our stromal biology expertise [7,11-12], we are taking drug-repurposing approaches to test agents with effects on stromal biology in combination with current standard-of-care chemotherapies (Gemcitabine/Abraxane) to improve clinical outcomes.

 

Itraconazole is a widely available, FDA-approved antifungal that has potential anti-cancer effects, although its efficacy in the context of PC remains relatively unexplored. Itraconazole can perturb the Niemann-Pick C1 Protein (NPC1) receptor, downstream of the Akt/mTOR pathway – which is atypically activated in ~25% of pancreatic cancers, with NPC1 aberrations present in ~17% of pancreatic cancers. Our initial data shows differential NPC1 expression in our patient-derived models, and demonstrates that itraconazole efficacy is correlated with NPC1 and AKT levels in vitro. Our preliminary in vivo findings indicate that itraconazole, in combination with Gemcitabine/Abraxane, significantly improves survival in a personalised patient-derived xenograft setting. Excitingly, our data using a model of metastatic PC show that itraconazole hinders metastatic colonisation in the liver and significantly delays disease progression, while inhibiting immunosuppressive elements in the stroma and pro-tumourigenic signalling.

  1. [1] L. B. Alexandrov et al., ‘Signatures of mutational processes in human cancer’, Nature, vol. 500, no. 7463, pp. 415–421, Aug. 2013.
  2. [2] N. Waddell et al., ‘Whole genomes redefine the mutational landscape of pancreatic cancer’, Nature, vol. 518, no. 7540, pp. 495–501, Feb. 2015.
  3. [3] ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, ‘Pan-cancer analysis of whole genomes’, Nature, vol. 578, no. 7793, pp. 82–93, 2020.
  4. [4] E. Bowler et al., ‘Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells’, BMC Cancer, vol. 18, no. 1, p. 355, Dec. 2018.
  5. [5] P. Adamo et al., ‘The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells’, Oncol Lett, vol. 14, no. 5, pp. 5605–5610, Nov. 2017.
  6. [6] S. Uzor, P. Zorzou, E. Bowler, S. Porazinski, I. Wilson, and M. Ladomery, ‘Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention’, Gene, vol. 670, pp. 46–54, Sep. 2018.
  7. [7] A. Chou et al., ‘Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer’, Gut, vol. 67, no. 12, pp. 2142–2155, Dec. 2018.
  8. [8] S. L. Jumbe et al., ‘The Evolutionarily Conserved Cassette Exon 7b Drives ERG’s Oncogenic Properties’, Translational Oncology, vol. 12, no. 1, pp. 134–142, Jan. 2019.
  9. [9] L. Li et al., ‘Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer’, Br. J. Cancer, Jun. 2020.
  10. [10] T. Belali 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, vol. 1863, no. 12, p. 194642, Dec. 2020.
  11. [11] S. Porazinski et al., ‘YAP is essential for tissue tension to ensure vertebrate 3D body shape’, Nature, vol. 521, no. 7551, pp. 217–221, May 2015.
  12. [12] C. Vennin et al., ‘Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis’, Science Translational Medicine, vol. 9, no. 384, p. eaai8504, Apr. 2017.