title: Metabolic response of prostate cancer to nicotinamide phophoribosyltransferase inhibition in a hyperpolarized MR/PET compatible bioreactor.
abstract: BACKGROUND
  Metabolic shifts in disease are of great interest for the development of novel therapeutics. In cancer treatment, these therapies exploit the metabolic phenotype associated with oncogenesis and cancer progression. One recent strategy involves the depletion of the cofactors needed to maintain the high rate of glycolysis seen with the Warburg effect. Specifically, blocking nicotinamide adenine dinucleotide (NAD) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) inhibition depletes cancer cells of the NAD needed for glycolysis. To characterize this metabolic phenotype in vivo and describe changes in flux with treatment, non-invasive biomarkers are necessary. One such biomarker is hyperpolarized (HP) [1-(13) C] pyruvate, a clinically translatable probe that allows real-time assessment of metabolism.
  
  
  METHODS
  We therefore developed a cell perfusion system compatible with HP magnetic resonance (MR) and positron emission tomography (PET) to develop translatable biomarkers of response to NAMPT inhibition in reduced volume cell cultures.
  
  
  RESULTS
  Using this platform, we observed a reduction in pyruvate flux through lactate dehydrogenase with NAMPT inhibition in prostate cancer cells, and showed that both HP lactate and 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) can be used as biomarkers for treatment response of such targeted agents. Moreover, we observed dynamic flux changes whereby HP pyruvate was re-routed to alanine, providing both positive and negative indicators of treatment response.
  
  
  CONCLUSIONS
  This study demonstrated the feasibility of a MR/PET compatible bioreactor approach to efficiently explore cell and tissue metabolism, the understanding of which is critical for developing clinically translatable biomarkers of disease states and responses to therapeutics.
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York.|Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York.
authors.forename: Kayvan R
authors.initials: KR
authors.lastname: Keshari
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Van Criekinge
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: Renuka
authors.initials: R
authors.lastname: Sriram
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: Bertram L
authors.initials: BL
authors.lastname: Koelsch
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: Zhen J
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.affiliation: Department of Urology, Stanford University, Stanford, California.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Department of Biomedical Imaging, Genentech Inc., South San Francisco, California.
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Kurhanewicz
mesh_terms: D019149:Bioreactors; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: MRS; NAMPT; metabolic flux; metabolism; translational biomarkers