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Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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ELGOGARY, Amira, Qingguo XU, Brad POORE, Jesse ALT, Sarah C. ZIMMERMANN, Liang ZHAO, Jie FU, Baiwei CHEN, Thomas HARTUNG, Anne LE, 2016. Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. In: Proceedings of the National Academy of Sciences. 113(36), pp. E5328-E5336. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1611406113

@article{Elgogary2016Combi-36770, title={Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer}, year={2016}, doi={10.1073/pnas.1611406113}, number={36}, volume={113}, issn={0027-8424}, journal={Proceedings of the National Academy of Sciences}, pages={E5328--E5336}, author={Elgogary, Amira and Xu, Qingguo and Poore, Brad and Alt, Jesse and Zimmermann, Sarah C. and Zhao, Liang and Fu, Jie and Chen, Baiwei and Hartung, Thomas and Le, Anne} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/36770"> <dc:contributor>Poore, Brad</dc:contributor> <dc:creator>Le, Anne</dc:creator> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Hartung, Thomas</dc:creator> <dc:creator>Elgogary, Amira</dc:creator> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Zimmermann, Sarah C.</dc:creator> <dc:contributor>Elgogary, Amira</dc:contributor> <dc:contributor>Fu, Jie</dc:contributor> <dc:creator>Xu, Qingguo</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2017-01-18T07:09:09Z</dc:date> <dc:contributor>Le, Anne</dc:contributor> <dcterms:abstract xml:lang="eng">Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.</dcterms:abstract> <dc:creator>Fu, Jie</dc:creator> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Alt, Jesse</dc:contributor> <dc:creator>Poore, Brad</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2017-01-18T07:09:09Z</dcterms:available> <dc:contributor>Hartung, Thomas</dc:contributor> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/36770"/> <dc:contributor>Chen, Baiwei</dc:contributor> <dc:contributor>Zhao, Liang</dc:contributor> <dc:contributor>Zimmermann, Sarah C.</dc:contributor> <dcterms:title>Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer</dcterms:title> <dcterms:issued>2016</dcterms:issued> <dc:contributor>Xu, Qingguo</dc:contributor> <dc:language>eng</dc:language> <dc:creator>Alt, Jesse</dc:creator> <dc:creator>Chen, Baiwei</dc:creator> <dc:creator>Zhao, Liang</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> </rdf:Description> </rdf:RDF>

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