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)
| Autor: | Catherine Berset, Hanne Hawle, Ulrich Mey, Felicitas Hitz, Gregoire Berthod, Alwin D. R. Huitema, Dagmar Hess, Jürgen Bader, Thomas Pabst, Hilde Rosing, Markus Joerger, Marianne Kraus, Alexandros Xyrafas, Christoph Driessen, Christiana Sessa, Roger von Moos, Hermann S. Overkleeft |
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| Přispěvatelé: | University of Zurich, Driessen, Christoph |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Proteasome Endopeptidase Complex Lymphoma 2720 Hematology 610 Medicine & health Antineoplastic Agents Pharmacology Drug Administration Schedule Bortezomib 03 medical and health sciences 0302 clinical medicine immune system diseases Antineoplastic Combined Chemotherapy Protocols medicine HIV Protease Inhibitor Humans Protease inhibitor (pharmacology) Multiple myeloma Aged Leukemia Nelfinavir business.industry Hematology Articles HIV Protease Inhibitors Middle Aged medicine.disease 3. Good health Drug Combinations 030104 developmental biology Treatment Outcome Drug Resistance Neoplasm 030220 oncology & carcinogenesis Toxicity 10032 Clinic for Oncology and Hematology Proteasome inhibitor Unfolded protein response Leukocytes Mononuclear Unfolded Protein Response Female business Multiple Myeloma medicine.drug |
| Zdroj: | Haematologica Haematologica, 101(3), 346-55 Haematologica, 101(2), 346-355 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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