Poster Presentation 36th Lorne Cancer Conference 2024

Use of novel discoidin domain receptor inhibitors as a potential anti-fibrotic in pancreatic cancer (#116)

Diana Schuhmacher 1 2 , Henry Barraclough-Franks 1 2 , Emer Cahill 1 , Diego Chacon-Fajardo 1 2 , Aji Istadi 1 2 , Silvia Lombardi 1 , Johana Luhur 1 2 , Yasir Mahmood 1 , Benjamin McLean 1 2 , Cathy Wang 1 , Sean Porazinski 1 2 , Marina Pajic 1 2
  1. The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Pancreatic cancer (PC), with its overall 5-year survival rate of less than 10% in Australia, is projected to become the second leading cause of cancer death within a decade1. A major factor that reduces efficacy of current standard of care treatments for PC is dysregulation of the tumour microenvironment, leading to extensive desmoplasia, reduced stromal vascularisation, and immune suppression. Intense fibrosis at tumour sites, desmoplasia, is due to increased deposition of extracellular matrix (ECM) components by stromal cells (cancer-associated fibroblasts and pancreatic stellate cells), and results in a rigid barrier around the tumour, protecting it from chemotherapy2. Thus, breaking down desmoplasia around pancreatic tumours is an attractive target for drug development to improve conventional chemotherapy effectiveness.

Discoidin domain receptors 1 and 2 (DDR1/2) are collagen activated receptor tyrosine kinases (RTKs) and play important roles in numerous signalling pathways and normal physiological processes, including development and wound healing. However, they have also been reported to promote tumorigenesis and metastasis by promoting ECM remodelling, cancer cell invasion, and drug resistance in a variety of cancers, including PC3. Based on this knowledge, we hypothesise that inhibition of DDR1/2 may reduce desmoplasia and decrease chemoresistance in PC. However, current DDR inhibitors are general non-specific RTK inhibitors, and have off-target effects resulting in unwanted side effects. Using novel small molecule DDR1/2-specific inhibitors (in collaboration with Redx Pharma) and in vitro and in vivo models of fibrotic PC validated in our laboratory, we aim to investigate the effects of specific DDR1/2 inhibition on collagen remodelling, and fibrotic tumour formation and chemoresistance. By inhibiting DDR1/2, we may reduce the severity of fibrosis in the tumour microenvironment of PC and improve the efficacy of current standard of care chemotherapy.

  1. 1. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495-501, doi:10.1038/nature14169 (2015).
  2. 2. Smith, C. et al. Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy. World J Gastroenterol 28, 3297-3313, doi:10.3748/wjg.v28.i27.3297 (2022).
  3. 3. Mehta, V., Chander, H. & Munshi, A. Complex roles of discoidin domain receptor tyrosine kinases in cancer. Clin Transl Oncol 23, 1497-1510, doi:10.1007/s12094-021-02552-6 (2021).