title: Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma.
abstract: Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multimodality approach to evaluate the phenotypic effects and metabolic changes that occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate productionin vitro, followed by cell growth inhibition.In vivo, we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas.Cancer Res; 77(11); 3113-20. ©2017 AACR.
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Gialleonardo
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hannah N
authors.initials: HN
authors.lastname: Aldeborgh
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vesselin
authors.initials: V
authors.lastname: Miloushev
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Folkers
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kristin
authors.initials: K
authors.lastname: Granlund
authors.affiliation: Medicine Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Medicine Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.affiliation: Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. rahimikk@mskcc.org.|Weill Cornell Medical College, New York, New York.
authors.forename: Kayvan R
authors.initials: KR
authors.lastname: Keshari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D012509:Sarcoma / Q000000981:diagnostic imaging*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays