title: Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).
abstract: Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland christoph.driessen@kssg.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kraus
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bader
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Hitz
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Berset
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Xyrafas
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Hanne
authors.initials: H
authors.lastname: Hawle
authors.affiliation: University Hospital CHUV, Lausanne, Switzerland.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Berthod
authors.affiliation: University of Leiden, the Netherlands.
authors.forename: Hermann S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: San Giovanni hospital, Bellinzona, Switzerland.
authors.forename: Christiana
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Alwin
authors.initials: A
authors.lastname: Huitema
authors.affiliation: Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Hematology & Medical Oncology, Kantonsspital Graubuenden, Chur, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hess
authors.affiliation: Hematology & Medical Oncology, Kantonsspital Graubuenden, Chur, Switzerland.
authors.forename: Ulrich J M
authors.initials: UJ
authors.lastname: Mey
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069286:Bortezomib / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019888:Nelfinavir / Q000493:pharmacokinetics / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D016896:Treatment Outcome; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D019888:Nelfinavir