Poster Presentation 31st Lorne Cancer Conference 2019

Metabolically Reprograming Pancreatic Stellate Cells using a Novel Nanomedicine for the Treatment of Pancreatic Cancer (#369)

George Sharbeen 1 , Anouschka Akerman 1 , Joshua McCarroll 2 3 , Cyrille Boyer 3 , Jeff Holst 4 , Janet Youkhana 1 , Jennifer Morton 5 , Tom Davis 6 , David Goldstein 1 , Mert Erkan 7 , Phoebe Phillips 1 3
  1. Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
  2. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
  3. Australian Centre for NanoMedicine, UNSW Sydney, Sydney, NSW, Australia
  4. Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
  5. Beatson Institute, Cancer Research UK, Glasgow, UK
  6. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
  7. Department of Surgery, Koc University, School of Medicine, Istanbul, Turkey

Background: Pancreatic cancer (PC) is a lethal disease characterised by extensive fibrosis that distorts tumor vasculature creating hypoxia/oxidative stress (OS). This drives PC tumor progression and chemoresistance, and impedes drug delivery. Cancer-associated pancreatic stellate cells (CA-PSCs) orchestrate fibrosis and promote PC growth/metastases, making them key therapeutic targets. Solute carrier 7A11 (SLC7A11) is part of the xCT transport system that controls cystine uptake, required for glutathione (antioxidant) synthesis. We have shown SLC7A11 is upregulated in CA-PSCs, compared to normal human PSCs. We hypothesised that SLC7A11 inhibition will reduce CA-PSC survival and resistance to oxidative stress.

Aims: To assess the effect of SLC7A11 inhibition on (1) CA-PSC growth and metabolism in vitro and (2) pancreatic tumor growth in vivo using a nanomedicine.

Methods: (1) Human patient-derived CA-PSCs (n=3-5) were transfected with control or SLC7A11-siRNA ± oxidative stress (t-butyl hydroperoxide; tBHP) and viability (trypan blue exclusion), SLC7A11 function (14C-cystine uptake; glutathione), and intracellular OS (CellROX) were measured. (2) Orthotopic PC tumors (PC+CA-PSCs) in mice were treated with control or SLC7A11-siRNA coupled to our novel nanoparticle (Biomacromolecules, 17;2337-51, 2016). Tumor volume and fibrosis (Sirius red) was measured.

Results: (1) SLC7A11-siRNA reduced CA-PSC proliferation (62.2±7.5% of control-siRNA; p<0.01) and oxidative stress enhanced this effect (7.6±2.6% of control-siRNA; p<0.0001). SLC7A11 inhibition reduced CA-PSC cystine uptake (51.8±8.8% of control; p<0.05) and intracellular glutathione (40.0±9.6% of control; p<0.01), and increased intracellular OS (166.4±26.8% of control-siRNA+tBHP; p<0.05). (2) SLC7A11 knockdown in orthotopic PC tumors significantly decreased tumor growth (43.9±23.1% decrease; p<0.05) and fibrosis (45.6±12.3% decrease; p<0.05), relative to controls.

Conclusions: (1) SLC7A11 regulates CA-PSC proliferation and sensitivity to oxidant stress. (2) Inhibition of SLC7A11 in PC tumors can reduce their growth and alleviate fibrosis. Therapeutic inhibition of SLC7A11 in PC using our novel nanomedicine could potentially improve PC patient outcomes by reducing tumor growth, and reprogramming CA-PSCs and fibrosis.