Poster Presentation 31st Lorne Cancer Conference 2019

A novel therapeutic approach to inhibit the oncogenic cross-talk between pancreatic cancer cells and the surrounding stroma (#404)

Bekesho G. Wendimu 1 , Kyung C. Park 1 , Patric J. Jansson 1 , Minoti Apte 2 , Des R. Richardson 1 , Zaklina Kovacevic 1
  1. Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales 2006, Australia
  2. Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

Background: Pancreatic cancer (PaCa) is a leading cause of cancer-related deaths and projected to be the second most common cancer in a decade. It is characterized by a dense stroma surrounding tumor cells, known as desmoplasia, that is stimulated by various factors released by PaCa cells including Hepatocyte Growth Factor (HGF) and Insulin-like Growth Factor Receptor (IGF-1). Stromal cells, in turn, release mitogenic substances that stimulate tumor growth, invasion, and resistance to therapy.

We investigated the potential of targeting the metastasis suppressor gene NDRG1 to interrupt the oncogenic cross-talk between cancer associated human pancreatic stellate cells (CAhPSCs) and PaCa cells.

Methods: We assessed novel thiosemicarbazone anti-cancer agents, Dp44mT and DpC, that up-regulate NDRG1 and their effects on: (i) HGF and IGF-1 production by CAhPSC; (ii) HGF and IGF-1 receptors on PaCa cells and their down-stream signaling networks, and; (iii) proliferative and metastatic properties of PaCa cells when co-cultured with CAhPSCs in vitro and in vivo.

Results: Dp44mT and DpC up-regulated NDRG1 and reduced the production of HGF and IGF-1 by CAhPSCs. These agents also inhibited the down-stream HGF and IGF-1 signaling pathways and reduced the metastatic potential of PaCa cells in the presence of CAhPSC secretions. NDRG1 over-expression alone had similar effects, while silencing NDRG1 further potentiated the oncogenic cross-talk between PaCa and CAhPSC cells.

Conclusions: Novel agents targeting NDRG1 have the unique ability to block the oncogenic cross-talk between PaCa cells and the surrounding stroma. This presents a novel approach to PaCa treatment that can potentially overcome the major problems attributed to desmoplasia, including therapeutic resistance and metastasis.