Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Anticancer efficacy of the hypoxia–activated prodrug TH-302 in a preclinical model of osteosarcoma development and metastasis. (#217)

Vasilios Liapis 1 , Agatha Labrinidis 1 , Shelley Hay 1 , Irene Zinonos 1 , Vasilios Panagopoulos 1 , Mark O DeNichilo 1 , Vladimir Ponomarev 2 , Gerald J Atkins 3 , David M Findlay 3 , Andrew CW Zannettino 4 , Andreas Evdokiou 1
  1. Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, South Australia, Australia
  2. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, USA
  3. Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, South Australia, Australia
  4. Myeloma and Mesenchymal Research Laboratory, Bone and Cancer Laboratories, Division of Haematology, Hanson Institute, Adelaide, South Australia, Australia

Tumour hypoxia is a major cause of treatment failure for a wide variety of malignancies. Tumour hypoxia leads to resistance to anticancer chemotherapy and radiotherapy and predisposes to increased malignancy and tumour metastasis. However, despite its adverse effects upon tumour response to treatment, hypoxia offers several opportunities for the development of new cancer therapeutics.
TH-302 is a hypoxia-activated pro-drug that displays potent hypoxia-dependent cytotoxicity. In this study, we investigated the cytotoxic activity of TH-302 in a panel of osteosarcoma (OS) cell lines (K-HOS, BTK-143, MSK-8G) in vitro and evaluated its anticancer efficacy in a preclinical model of osteosarcoma development progression and metastasis. In vitro, TH-302 treatment exerted significant dose-dependent cytotoxicity, only under hypoxic conditions whereas; normal primary human osteoblasts were relatively resistant.
To test the efficacy of TH-302 in vivo, K-HOS human OS cells, tagged with a luciferase reporter construct, were transplanted directly into the tibial marrow cavity of nude mice. Tumour development in bone and subsequent lung metastases with and without TH-302 treatment was monitored in live animals and in real time using bioluminescence imaging and histology, whereas the development of OS induced bone destruction was measured using high resolution micro-computer tomography. TH-302 monotherapy reduced tumour burden in bone and protected the bone from OS-induced bone destruction. Importantly, this translated to a 50% reduction in the incidence of lung metastases. TH-302 treatment was selectively toxic to cancer cells in bone, as evidenced by strong TUNEL positivity in a large portion of the tumour mass whereas osteoblasts, osteocytes, osteoclasts or chondrocytes were unaffected.
These results show that TH-302 is a potent agent with strong activity against the development, progression and metastatic spread of OS and provide supporting evidence that targeting the intrinsically hypoxic bone marrow niche is a useful strategy for the treatment of skeletal malignancy.