title: Metabolomics strategy reveals subpopulation of liposarcomas sensitive to gemcitabine treatment.
abstract: Unlike many cancers that exhibit glycolytic metabolism, high-grade liposarcomas often exhibit low 2[18F]fluoro-2-deoxy-D-glucose uptake by positron emission tomography (PET), despite rapid tumor growth. Here, we used liquid chromatography tandem mass spectrometry to identify carbon sources taken up by liposarcoma cell lines derived from xenograft tumors in patients. Interestingly, we found that liposarcoma cell lines consume nucleosides from culture media, suggesting nucleoside salvage pathway activity. The nucleoside salvage pathway is dependent on deoxycytidine kinase (dCK) and can be imaged in vivo by PET with 1-(2'-deoxy-2'-[18F]fluoroarabinofuranosyl) cytosine (FAC). We found that liposarcoma cell lines and xenograft tumors exhibit dCK activity and dCK-dependent FAC uptake in vitro and in vivo. In addition, liposarcoma cell lines and xenograft tumors are sensitive to treatment with the nucleoside analogue prodrug gemcitabine, and gemcitabine sensitivity is dependent on dCK expression. Elevated dCK activity is evident in 7 of 68 clinical liposarcoma samples analyzed. These data suggest that a subpopulation of liposarcoma patients have tumors with nucleoside salvage pathway activity that can be identified noninvasively using [18F]-FAC-PET and targeted using gemcitabine.
  
  
  CONCLUSIONS
  Patients with high-grade liposarcoma have poor prognoses and often fail to respond to chemotherapy. This report identifies elevated nucleoside salvage activity in a subset of liposarcomas that are identifiable using noninvasive PET imaging with FAC and that are sensitive to gemcitabine. Thus, we suggest a new treatment paradigm for liposarcoma patients that uses [18F]-FAC-PET in the clinic to delineate gemcitabine responders from nonresponders.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.forename: Ethan
authors.initials: E
authors.lastname: Ahler
authors.forename: Brenna
authors.initials: B
authors.lastname: Tam
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.forename: Mirielle
authors.initials: M
authors.lastname: Riedinger
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Benz
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Smith
authors.forename: Fritz C
authors.initials: FC
authors.lastname: Eilber
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine