Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302
Bibliographic record
Abstract
// Ines Lohse 1 , Joanna Rasowski 1 , Pinjiang Cao 1 , Melania Pintilie 1 , Trevor Do 1,6,7 , Ming-Sound Tsao 1,2,3 , Richard P. Hill 1,4,5 and David W. Hedley 1,4,8,9 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".