Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302

Persistent Link:
http://hdl.handle.net/10150/610264
Title:
Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302
Author:
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.
Affiliation:
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
Issue Date:
2016-05-20
Publisher:
BioMed Central
Citation:
Wojtkowiak et al. Cancer & Metabolism (2015) 3:2 DOI 10.1186/s40170-014-0026-z
Journal:
Cancer & Metabolism
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)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
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.
EISSN:
2049-3002
DOI:
10.1186/s40170-014-0026-z
Keywords:
Hypoxia; Hypoxia-activated prodrugs; TH-302; Tumor microenvironment; Metabolism; Pancreatic cancer; Functional imaging; Computational modeling
Version:
Final published version
Additional Links:
http://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-014-0026-z

Full metadata record

DC FieldValue Language
dc.contributor.authorWojtkowiak, Jonathan W.en
dc.contributor.authorCornnell, Heather C.en
dc.contributor.authorMatsumoto, Shingoen
dc.contributor.authorSaito, Keitaen
dc.contributor.authorTakakusagi, Yoichien
dc.contributor.authorDutta, Prasantaen
dc.contributor.authorKim, Munjuen
dc.contributor.authorZhang, Xiaomengen
dc.contributor.authorLeos, Rafaelen
dc.contributor.authorBailey, Kate M.en
dc.contributor.authorMartinez, Garyen
dc.contributor.authorLloyd, Mark C.en
dc.contributor.authorWeber, Craigen
dc.contributor.authorMitchell, James B.en
dc.contributor.authorLynch, Ronald M.en
dc.contributor.authorBaker, Amanda F.en
dc.contributor.authorGatenby, Robert A.en
dc.contributor.authorRejniak, Katarzyna A.en
dc.contributor.authorHart, Charlesen
dc.contributor.authorKrishna, Murali C.en
dc.contributor.authorGillies, Robert J.en
dc.date.accessioned2016-05-20T09:02:34Z-
dc.date.available2016-05-20T09:02:34Z-
dc.date.issued2016-05-20-
dc.identifier.citationWojtkowiak et al. Cancer & Metabolism (2015) 3:2 DOI 10.1186/s40170-014-0026-zen
dc.identifier.doi10.1186/s40170-014-0026-zen
dc.identifier.urihttp://hdl.handle.net/10150/610264-
dc.description.abstractBACKGROUND: 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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-014-0026-zen
dc.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)en
dc.subjectHypoxiaen
dc.subjectHypoxia-activated prodrugsen
dc.subjectTH-302en
dc.subjectTumor microenvironmenten
dc.subjectMetabolismen
dc.subjectPancreatic canceren
dc.subjectFunctional imagingen
dc.subjectComputational modelingen
dc.titlePyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302en
dc.typeArticleen
dc.identifier.eissn2049-3002en
dc.contributor.departmentDepartment of Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Instituteen
dc.contributor.departmentCenter for Cancer Research, National Cancer Instituteen
dc.contributor.departmentDepartment of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Instituteen
dc.contributor.departmentArizona Cancer Center, College of Medicine, University of Arizonaen
dc.contributor.departmentHematology/Oncology Section, College of Medicine, University of Arizonaen
dc.contributor.departmentAnalytic Microscopy Core Facility, H. Lee Moffitt Cancer Center and Research Instituteen
dc.contributor.departmentDepartment of Physiology, College of Medicine, University of Arizonaen
dc.contributor.departmentDepartment of Radiology, H. Lee Moffitt Cancer Center and Research Instituteen
dc.contributor.departmentDepartment of Oncologic Sciences, University of South Floridaen
dc.contributor.departmentThreshold Pharmaceuticalen
dc.identifier.journalCancer & Metabolismen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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