Poster Presentation 28th Lorne Cancer Conference 2016

Optimising LOX-based ECM-targeted therapy in pancreatic cancer with Gemcitabine and Abraxane using live biosensor imaging (#273)

Sean C Warren 1 , Claire Venin 1 , Astrid Magenau 1 , Amr Allam 1 , Mark Pinese 1 , Andrew V Biankin 1 , David Herrmann 1 , James Conway 1 , Lena Wullkopf 1 , Morghan Lucas 1 , Janine T Erler 2 , TR Jeffrey Evans 3 , Owen Sansom 3 , Kurt I Anderson 3 , Jennifer Morton 3 , Marina Pajic 1 , Paul Timpson 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark
  3. Cancer Research UK Beatson Institute, Glasgow, UK

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality, in part due to its limited response to current cheomotherapies. In a recent study [1], we identified a Lysyl oxidase (LOX)/hypoxia genetic signature associated with poor patient survival in resectable patients. It was found that expression of LOX, an extracellular protein which strengthens the extracellular matrix by crosslinking collagen, is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. LOX inhibition synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. Lox inhibition lead to alterations in the stromal microstructure, including increased vasculature and decreased fibrillar collagen, potentially reversing many of the features leading to the resistance of PDAC to conventional therapies.

In this study we aim to investigate whether antibody-based inhibition of LOX is a suitable strategy for improving anti-invasive therapeutic outcome in human pancreatic cancer. We have stratified 84 patient-derived pancreatic xenografts tumours using genetic profiling based on enhanced expression of Lox and ECM signatures and second harmonic generation (SHG) imaging of tissue microarray cores to assess the level of collagen deposition and crosslinking. By combining these readouts we aim to identify a subset of the tumours that may prove to be susceptible to combination therapy of the Lox-targeting antibody and the standard-of-care chemotherapy, Gemcitabine and Abraxane (GemAbrax).

To assess the efficacy of combination anti-LOX/GemAbrax therapy we will use intravital imaging of xenografts from pancreatic cancer cell lines derived from the selected patient tumours. In addition to monitoring the level of locally invasive tumour formation and overall survival, we will monitor the ECM integrity and ultrastructure using SHG imaging and use the cell cycle reporter FUCCI [2] to assess drug activity in the tumour.

  1. Miller, B.W., et al., Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med, 2015. 7(8): p. 1063-76.
  2. Sakaue-Sawano, A., et al., Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell, 2008. 132(3): p. 487-98.