Poster Presentation 26th Lorne Cancer Conference 2014

PG545, a heparan sulfate mimetic, targets the tumour microenvironment to potently inhibit solid tumour growth and metastasis, alone and in combination with chemotherapy, in models of pancreatic and ovarian cancer. (#134)

Keith Dredge 1 , Boris Winterhoff 2 , Luisa Freyer 3 , Attila Teoman 2 , Shailendra Giri 4 , Antonia von Bismarck 3 , Robert Hoffman 3 , Jacie Maguire 5 , Jeremy Chien 6 , Matthew Block 7 , Deok-Beom Jung 8 , Miyong Yun 8 , Sung-Hoon Kim 8 , Michael Millward 9 , Darryn Bampton 1 , Edward Hammond 1 , Viji Shridhar 2
  1. Progen Pharmaceuticals Ltd., Brisbane, QLD, Australia
  2. Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA
  3. Dept of Experimental Pathology, Mayo Clinic, Rochester, MN, USA
  4. Neurology Research, Henry Ford Health System, Detroit, MI, USA
  5. Dept of Obstretrics and Gynaecology, University of Minnesota, Minneapolis, MN, USA
  6. Dept of Cancer Biology, University of Kansas, Kansas, KS, USA
  7. Dept of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
  8. Cancer Preventive Material Development Research Centre , Kyunghee University, Seoul, Doandaemun-Gu, South Korea
  9. Dept of Medical Oncology, Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia

The translational promise of developing agents which target the tumour microenvironment remains a significant challenge as exemplified by resistance to anti-angiogenic therapy and emergence of metastatic phenotypes which contribute to poor survival outcomes. Heparan sulfate (HS), as part of the extracellular matrix regulates several aspects of cancer biology and cleavage of HS by the endo-ß-glucuronidase heparanase facilitates angiogenesis and metastasis. Competitive inhibition of heparanase by PG545, in addition to its modulation of angiogenic growth factors, is considered a key differentiator from other anti-angiogenic agents. Herein, we demonstrate the unique activities of PG545 and its utility with existing agents, specifically in models of pancreatic and ovarian cancer. First, using models of pancreatic adenocarcinoma (orthotopic AsPC-1 and MiaPaCa-2, and a GEMM of PDAC), PG545 significantly reduced solid tumour growth, metastasis and induced hypoxia but without leading to collagen deposition or epithelial-to-mesenchymal transition (EMT). PG545 therapy also reduced tumour-associated macrophage and myeloid derived suppressor cell number. Combination with gemacitabine showed additive anti-tumour activity in AsPC1 mice. Second, single-agent PG545 significantly reduced tumour progression and/or ascites formation in syngeneic (C200 and ID8) and xenogeneic models (A2780) of ovarian cancer. Changes in plasma VEGF and/or heparanase were considered indicative of a pharmacodynamic effect - also observed following PG545 treatment to patients in a previous clinical trial, further illustrating the translational relevance of these studies. Moreover, significant additive activity was observed in combination with paclitaxel or cisplatin/carboplatin whilst imaging studies revealed PG545’s utility as a maintenance therapy following cisplatin and paclitaxel. Although single agent PG545 almost doubled median survival to 43 days, as part of a maintenance therapy, 90% of mice were alive beyond 60 days. Thus, using PG545 alone and in combination, via multiple effects within the tumour microenvironment, has the potential to provide greater long-term suppression of angiogenesis in tumours than pathway-specific inhibitors. A Phase I trial in advanced cancer patients is expected to commence soon.