title: Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer.
abstract: 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.
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Amira
authors: A
authors: Elgogary
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Qingguo
authors: Q
authors: Xu
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Brad
authors: B
authors: Poore
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Jesse
authors: J
authors: Alt
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Sarah C
authors: SC
authors: Zimmermann
authors: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
authors: Liang
authors: L
authors: Zhao
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Jie
authors: J
authors: Fu
authors: Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Baiwei
authors: B
authors: Chen
authors: Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, MD 21218;
authors: Shiyu
authors: S
authors: Xia
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Yanfei
authors: Y
authors: Liu
authors: Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Marc
authors: M
authors: Neisser
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Christopher
authors: C
authors: Nguyen
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Ramon
authors: R
authors: Lee
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Joshua K
authors: JK
authors: Park
authors: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Juvenal
authors: J
authors: Reyes
authors: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; Center for Alternatives to Animal Testing, University of Konstanz, Konstanz 78464, Germany;
authors: Thomas
authors: T
authors: Hartung
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Camilo
authors: C
authors: Rojas
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Rana
authors: R
authors: Rais
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Takashi
authors: T
authors: Tsukamoto
authors: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; gsemenza@jhmi.edu hanes@jhmi.edu bslusher@jhmi.edu annele@jhmi.edu.
authors: Gregg L
authors: GL
authors: Semenza
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Wilmer Eye Institute Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, MD 21218; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205; gsemenza@jhmi.edu hanes@jhmi.edu bslusher@jhmi.edu annele@jhmi.edu.
authors: Justin
authors: J
authors: Hanes
authors: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu hanes@jhmi.edu bslusher@jhmi.edu annele@jhmi.edu.
authors: Barbara S
authors: BS
authors: Slusher
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; gsemenza@jhmi.edu hanes@jhmi.edu bslusher@jhmi.edu annele@jhmi.edu.
authors: Anne
authors: A
authors: Le
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D044482:Benzeneacetamides / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005972:Glutaminase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013440:Sulfides / Q000008:administration & dosage* / Q000737:chemistry; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D044482:Benzeneacetamides; C000593334:CB-839; C117307:KRAS protein, human; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005973:Glutamine; D008687:Metformin; D005972:Glutaminase; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutation; glucose metabolism; glutaminolysis; intratumoral hypoxia; pancreatic ductal adenocarcinoma