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

Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):E5328-36. doi: 10.1073/pnas.1611406113. Epub 2016 Aug 24.

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.

Keywords: KRAS mutation; glucose metabolism; glutaminolysis; intratumoral hypoxia; pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Benzeneacetamides / therapeutic use
  • Cell Line, Tumor
  • Glutaminase / antagonists & inhibitors
  • Glutamine / metabolism
  • Humans
  • Metformin / administration & dosage*
  • Mice
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Sulfides / administration & dosage*
  • Sulfides / chemistry
  • Thiadiazoles / administration & dosage*
  • Thiadiazoles / chemistry
  • Thiadiazoles / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Benzeneacetamides
  • CB-839
  • KRAS protein, human
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • Glutamine
  • Metformin
  • Glutaminase
  • Proto-Oncogene Proteins p21(ras)