TY - JOUR
T1 - Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer
AU - Elgogary, Amira
AU - Xu, Qingguo
AU - Poore, Brad
AU - Alt, Jesse
AU - Zimmermann, Sarah C.
AU - Zhao, Liang
AU - Fu, Jie
AU - Chen, Baiwei
AU - Xia, Shiyu
AU - Liu, Yanfei
AU - Neisser, Marc
AU - Nguyen, Christopher
AU - Lee, Ramon
AU - Park, Joshua K.
AU - Reyes, Juvenal
AU - Hartung, Thomas
AU - Rojas, Camilo
AU - Rais, Rana
AU - Tsukamoto, Takashi
AU - Semenza, Gregg L.
AU - Hanes, Justin
AU - Slusher, Barbara S.
AU - Le, Anne
N1 - Funding Information:
This work was supported by NIH Grants R01-CA193895 (to A.L., B.S.S., and J.H.), R03-DA032470 (to B.S.S.), R21-CA169757 (to A.L.), P30-MH075673 (to B.S.S.), UL1 TR001079 (to B.S.S.), F32CA200275 (to S.C.Z), and R21NS074151 (to T.T.). This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research, which is funded in part by Grant UL1 TR 001079 from the National Center for Advancing Translational Sciences, a component of the NIH, and NIH Roadmap for Medical Research.
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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.
AB - 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.
KW - Glucose metabolism|
KW - Kras mutation|intratumoral hypoxia
KW - Pancreatic ductal adenocarcinoma|glutaminolysis|
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U2 - 10.1073/pnas.1611406113
DO - 10.1073/pnas.1611406113
M3 - Article
C2 - 27559084
AN - SCOPUS:84986216573
SN - 0027-8424
VL - 113
SP - E5328-E5336
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -