title: Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens.
abstract: Toward our goal of personalized medicine, we comprehensively profiled pre-treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of 'universal response' pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA-damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib-based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti-myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly-diagnosed myeloma.
authors.affiliation: University of Chicago, Chicago, IL, USA.|Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Dytfeld
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Shaun
authors.identifier: http://orcid.org/0000-0003-1781-4601
authors.initials: S
authors.lastname: Rosebeck
authors.affiliation: Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Malathi
authors.initials: M
authors.lastname: Kandarpa
authors.affiliation: Center for Research Informatics, Computation Institute and Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Anoop
authors.initials: A
authors.lastname: Mayampurath
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Computational Medicine & Bioinformatics, Ann Arbor, MI, USA.
authors.forename: Dattatreya
authors.initials: D
authors.lastname: Mellacheruvu
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Mattina M
authors.initials: MM
authors.lastname: Alonge
authors.affiliation: Medical College of Georgia, Augusta, GA, USA.
authors.forename: Lambert
authors.initials: L
authors.lastname: Ngoka
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Jagoda
authors.initials: J
authors.lastname: Jasielec
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Center for Research Informatics, Computation Institute and Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Volchenboum
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D057285:Precision Medicine / Q000379:methods; D040901:Proteomics / Q000379:methods; D011719:Pyrazines / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D000077269:Lenalidomide
keywords: bortezomib; lenalidomide; multiple myeloma; proteomics