title: Elucidation of potential bortezomib response markers in mutliple myeloma patients.
abstract: Liquid chromatography coupled to mass spectrometry (LC/MS) was used to elucidate early biomarkers of bortezomib response in multiple myeloma patients. The change in serum myeloma M-protein level, maintained for a minimum of 6 weeks, is used as one of the main criteria to evaluate patient clinical response to therapy. The objective of this study was to identify biomarkers using LC/MS in order to predict patient response to bortezomib sooner and more accurately compared to serum M-protein levels. The plasma LC/MS biomolecular/biochemical profiles, comprised of thousands of endogenous small molecules, peptides and proteins, were determined for 10 multiple myeloma patients at predose and 24 h after initial dosing with bortezomib. The comparative analysis of the metabolic profiles of non-responders and partial responders provided an opportunity to investigate mechanisms related to disease progression and identify biomarkers related to drug response. The plasma levels of two potential efficacy response markers were significantly more abundant in the non-responsive patients compared to the responders at 24-h postdose. The potential response biomarkers, apolipoprotein C-I and apolipoprotein C-I', were identified by mass spectral analyses and confirmed by authentic protein standards based on MALDI-TOF MS/MS sequencing of proteolytic peptides.
authors.affiliation: Nextcea, Inc., 600 West Cummings Park, #6375, Woburn, MA 01801, United States. frank.hsieh@nextcea.com
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Hsieh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tengstrand
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Pekol
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerciolini
authors.forename: Gerald
authors.initials: G
authors.lastname: Miwa
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D053302:Apolipoprotein C-I / Q000097:blood* / Q000737:chemistry; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis / Q000737:chemistry; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002853:Chromatography, Liquid / Q000379:methods; D017322:Clinical Trials, Phase II as Topic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D008970:Molecular Weight; D009101:Multiple Myeloma / Q000628:therapy*; D020033:Protein Isoforms / Q000097:blood / Q000737:chemistry; D011719:Pyrazines / Q000627:therapeutic use*; D012015:Reference Standards; D015203:Reproducibility of Results; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000592:standards; D053719:Tandem Mass Spectrometry / Q000592:standards; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D053302:Apolipoprotein C-I; D015415:Biomarkers; D001798:Blood Proteins; D001897:Boronic Acids; D020033:Protein Isoforms; D011719:Pyrazines; D000069286:Bortezomib