Oral Presentation 29th Lorne Cancer Conference 2017

Transient tissue ‘priming’ via ROCK manipulation uncouples pancreatic cancer progression, sensitivity to chemotherapy and the onset of the metastatic niche. (#39)

Claire Vennin 1 , Venessa Chin 2 , Sean Warren 2 , Morghan Lucas 2 , David Herrmann 1 , Pauline Melenec 2 , Stacey Walters 2 , Astrid Magenau 2 , Amr Allam 2 , Rachael McCloy 2 , James Conway 2 , Mark Pinese 2 , Celine Heu 3 , Ewan McGhee 4 , Renee Whan 3 , Shane Grey 2 , Amber L Johns 2 , Lorraine Chantrill 2 , Anthony J Gill 5 , Andrew V Biankin 4 , Yingxiao Wang 6 , Jeffry TR Evans 4 , Kurt I Anderson 4 , Michael S Samuel 7 , Andrew Burgess 2 , Owen J Sansom 4 , Jennifer P Morton 4 , Marina Pajic 2 , Paul Timpson 2
  1. Kinghorn Cancer Center Sydney, Darlinghurst, NSW, Australia
  2. The Kinghorn Cancer Center Sydney, Darlinghurst, NSW, Australia
  3. The Biomedical Imaging Facility - UNSW, Sydney
  4. The Beatson Institute, Glasgow
  5. Cancer Diagnosis and Pathology Research Group,, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney
  6. Department of Bioengineering, Institute of Engineering in Medicine, University of California , San Diego, USA
  7. Center for Cancer Biology, SA Pathology and the University of South Australia and School of Medicine, University of Adelaide, Adelaide

The emerging standard-of-care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, however patient response remains moderate.

Pancreatic cancer development and metastasis occur in complex settings with reciprocal feedback from micro-environmental cues influencing both disease progression and drug response. Recent studies assessing long-term, chronic targeting of the host tissue tension have yielded conflicting data on the utility of stromal targeting in limiting the progression of pancreatic cancer.

Here, we used intravital imaging to assess how transient manipulation of the tumour tissue, or ‘priming’, using the pharmaceutical Rho-kinase inhibitor Fasudil affects response to chemotherapy. Intravital FRET imaging of a CDK1 biosensor to monitor cytotoxic drugs efficacy revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites.

Transient priming also impaired extravasation efficiency and fibrotic niche remodelling within the liver, two important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived settings, highlighting that tailored fine-tuned tissue manipulation prior to chemotherapy may offer new opportunities in both primary and metastatic targeting of pancreatic cancer.