title: Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay.
abstract: While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56 mg/m(2) ), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow-derived CD138(+) tumour cells. Carfilzomib-induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near-complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Levitsky
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Bennett
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Shirin
authors.initials: S
authors.lastname: Arastu-Kapur
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Kellerman
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Tina F
authors.initials: TF
authors.lastname: Woo
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Alvin F
authors.initials: AF
authors.lastname: Wong
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: New York Presbyterian Hospital-Cornell Medical Center, New York, NY, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: Ashraf Z
authors.initials: AZ
authors.lastname: Badros
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: St. Vincent's Comprehensive Cancer Center, New York, NY, USA.
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.affiliation: Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Ahmann
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012074:Remission Induction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex
keywords: molecular analysis; multiple myeloma; myeloma therapy; pharmacology; trials