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

Amira Elgogary, Qingguo Xu, Brad Poore, Jesse Alt, Sarah C. Zimmermann, Liang Zhao, Jie Fu, Baiwei Chen, Shiyu Xia, Yanfei Liu, Marc Neisser, Christopher Nguyen, Ramon Lee, Joshua K. Park, Juvenal Reyes, Thomas Hartung, Camilo Rojas, Rana Rais, Takashi Tsukamoto, Gregg L. SemenzaJustin Hanes, Barbara S. Slusher, Anne Le

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E5328-E5336
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number36
DOIs
StatePublished - Sep 6 2016

Keywords

  • Glucose metabolism|
  • Kras mutation|intratumoral hypoxia
  • Pancreatic ductal adenocarcinoma|glutaminolysis|

ASJC Scopus subject areas

  • General

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