E-Poster Presentation 33rd Lorne Cancer Conference 2021

Epithelial versus stromal targeting of FAK in pancreatic cancer: deconstructing treatment regimens according to personal tumour status for improved outcome in personalised medicine (#136)

Kendelle J Murphy 1 2 , Daniel A Reed 1 , Claire Vennin 1 2 , James R.W Conway 1 2 , Max Nobis 1 2 , Cecilia R Chambers 1 , Brooke A Pereira 1 2 , Elysse C Fillipe 1 2 , Morghan C Lucas 1 , Sean C Warren 1 2 , Joanna N Skhinas 1 , Astrid Magneau 1 2 , Xanthe L Metcalf 1 , Janett Stoehr 1 , Gretel Major 1 , Ashleigh Parking 1 , Romain Bidanel 1 , Anaiis Zaratzian 1 , Andrew De Silva 1 , Lea Abdulkhalek 1 , Anthony J Gill 1 2 , Angela Chou 1 2 , Amber L Johns 1 , Andrew Burgess 3 , C Elizabth Caldon 1 2 , Lisa Horvath 1 , Roger Daly 4 , Nikolaj Gadegaard 5 , Andrew V Biankin 6 , Owen J Samsom 7 , Jennifer P Morton 7 , Yingxiao Wang 8 , Thomas R Cox 1 2 , Marina Pajic 1 2 , David Herrmann 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NEW SOUTH WALES, Australia
  2. St Vincents Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW, Australia
  3. ANZAC Research Institute , Sydney, NSW, Australia
  4. Monash Biomedicine Discovery Institute, Monash University , Melbourne, VIC, Australia
  5. School of Engineering, University of Glasgow, Glasgow, UK
  6. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  7. Cancer Research UK, Beatson Institute, Glasgow, UK
  8. Institute of Engineering in Medicine, University of California, San Diego, CA, USA

Pancreatic cancer is characterized by its aggressive metastatic nature and its resistance to common chemotherapy treatment with a dense, desmoplastic ECM that can both promote and prevent PDAC progression. The multifunctional protein FAK acts at the intersection of various signaling pathways often hijacked in cancer progression and metastasis and is a known regulator of ECM stiffness and mechano-signaling in both stromal and epithelial compartments. Here, we used intravital imaging in live tumors to visualize fine-tuned epithelial and stromal manipulation via FAK inhibitor (FAKi) priming to improve systemic chemotherapy whilst reducing metastatic spread in mouse and patient-derived PDAC models. Live tumor imaging of the FUCCI cell cycle reporter, in parallel with target validation via of FAK targeting via FRET-imaging of an FAK biosensor helped us to guide and optimize treatment response at both primary and secondary sites. Critically, fluid flow-induced shear-stress assessment and personalized patient-derived matrices also allowed us to deconstruct the benefits by which FAKi priming can reduce PDAC spread during disease progression and metastatic transit. Lastly, orthotopic stratification of PDAC patient samples from the Australian Pancreatic Genome Initiative (APGI) revealed a subset of patients that have poor prognosis and are likely to respond to FAKi priming regimens, where short-term stromal manipulation and epithelial FAK inhibition prior to chemotherapy may improve patient outcome and reduce the need for chronic combination therapy in PDAC.