Flash Talk and Poster Presentation 35th Lorne Cancer Conference 2023

Investigation of novel therapeutic targets in pancreatic cancer-associated fibrosis (#13)

Benjamin J McLean 1 , Sean Porazinski 1 , Aji Istadi 1 , Diego Chacon-Fajardo 1 , Emer Cahill 1 , Antonia Blackwell 1 , Yasir Mahmood 1 , Slivia Lombardi 1 , Eve Borbilas 1 , Payam Faizi Sobbi 1 , Kendelle Murphy 1 , Paul Timpson 1 , Marina Pajic 1
  1. Garvan Institute of Medical Research, Paddington, NSW, Australia

Pancreatic cancer (PC) lacks effective therapies for advanced disease and has a 10% 5-year survival rate. Given the genomic heterogeneity of PC1, personalized medicine approaches are a promising strategy to improve outcomes. In previous research we successfully targeted the stromal compartment2 to increase the efficacy of chemotherapy. Here we demonstrate dual anti-stromal, anti-tumour targeting using a novel small molecule Porcupine inhibitor, ‘PORCN-i’.

PORCN-i inhibits Wnt signaling by preventing Porcupine-mediated Wnt ligand activation. Wnt signalling features in the top 10 dysregulated pathways in PC1, driving PC progression, proliferation and survival of cancer cells. Wnt signalling creates a pro-tumorigenic microenvironment and promotes fibrosis by causing cancer associated fibroblast (CAF) activation and ECM deposition3,4. A potential marker of Wnt dependency, the RNF43 gene, negatively regulates Wnt signalling and is mutated in up to 10% of PC patients, who may therefore have Wnt-driven PDAC5.

PORCN-i reduces growth of RNF43 mutant (RNF43mut) subcutaneous tumours in patient derived xenograft (PDX) models, increasing apoptosis and reducing proliferation of tumour cells. Treated tumours show increased CAF activation and altered ECM composition, with decreases in key proteins (fibronectin, periostin) and changes to collagen remodelling. Furthermore, PORCN-i improves overall survival in clinically-relevant ‘priming’ (transient manipulation of tumour tissue before chemotherapy) and ‘chronic’ (administration alongside chemotherapy) regimens in combination with current standard-of-care Gemcitabine/Abraxane and FOLFIRINOX chemotherapies in an RNF43mut orthotopic PDX model. Additionally, PORCN-i prolongs survival in our RNF43mut PDX model of FOLFIRINOX resistance.

Excitingly, PORCN-i shows efficacy even in RNF43 WT models of PDAC. Orthotopically implanted immunocompetent KPC mice also show changes to ECM composition, as well as greater pro-inflammatory tumour-immune interactions. This is consistent with the emerging recognition that Wnt signalling regulates the immune TME6.

PORCN-i therefore shows strong translational potential to combat chemoresistance and for use in combination with immunotherapy. Ongoing work includes identification of tumour and stromal biomarkers of response to PORCN-i using cutting-edge in-house spatial transcriptomics tools and single cell transcriptomics. We are assessing the biological activity of PORCN-i in RNF43mut PC in phase-II monotherapy clinical trials, with comprehensive analysis of recruited PC patients to identify correlates of collective response to targeted therapy.

 

  1. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531: 47-52 (2016).
  2. Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Trans Med 9, (2017).
  3. Mosa, M. et al. A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer. Cancer Res 15(80): 5569-5582 (2020).
  4. Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun 3, 735 (2012).
  5. Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 110(31): 12649-12654 (2013)
  6. Hosein, A. et al. Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma. Gastroenterology. 162(4): 1303-1318 (2022)