BACKGROUND: Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. RESULTS: Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized 13C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors. CONCLUSIONS: Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/610264 |
| Date | 20 May 2016 |
| Creators | Wojtkowiak, Jonathan W., Cornnell, Heather C., Matsumoto, Shingo, Saito, Keita, Takakusagi, Yoichi, Dutta, Prasanta, Kim, Munju, Zhang, Xiaomeng, Leos, Rafael, Bailey, Kate M., Martinez, Gary, Lloyd, Mark C., Weber, Craig, Mitchell, James B., Lynch, Ronald M., Baker, Amanda F., Gatenby, Robert A., Rejniak, Katarzyna A., Hart, Charles, Krishna, Murali C., Gillies, Robert J. |
| Contributors | Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Center for Cancer Research, National Cancer Institute, Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Arizona Cancer Center, College of Medicine, University of Arizona, Hematology/Oncology Section, College of Medicine, University of Arizona, Analytic Microscopy Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Department of Physiology, College of Medicine, University of Arizona, Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncologic Sciences, University of South Florida, Threshold Pharmaceutical |
| Publisher | BioMed Central |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2015 Wojtkowiak et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) |
| Relation | http://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-014-0026-z |
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