Oncotarget

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Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302

Ines Lohse, Joanna Rasowski, Pinjiang Cao, Melania Pintilie, Trevor Do, Ming-Sound Tsao, Richard P. Hill and David W. Hedley _

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Oncotarget. 2016; 7:33571-33580. https://doi.org/10.18632/oncotarget.9654

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Abstract

Ines Lohse1, Joanna Rasowski1, Pinjiang Cao1, Melania Pintilie1, Trevor Do1,6,7, Ming-Sound Tsao1,2,3, Richard P. Hill1,4,5 and David W. Hedley1,4,8,9

1 Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

2 Department of Pathology, University Health Network, Toronto, Ontario, Canada

3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

4 Department of Medical Biophysics, Toronto, Ontario, Canada

5 Department of Radiation Oncology, Toronto, Ontario, Canada

6 Department of Radiation Medicine Program, Toronto, Ontario, Canada

7 Department of STTARR Innovation Center, Toronto, Ontario, Canada

8 Department of Medicine, University of Toronto, Toronto, Ontario, Canada

9 Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

Correspondence to:

David W. Hedley, email:

Keywords: pancreatic cancer, tumor-initiating cells, hypoxia, TH-302, patient-derived xenograft

Received: March 13, 2016 Accepted: May 16, 2016 Published: May 29, 2016

Abstract

Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).

The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.


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