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)
Christoph Driessen,
Marianne Kraus,
Markus Joerger,
Hilde Rosing,
Jürgen Bader,
Felicitas Hitz,
Catherine Berset,
Alexandros Xyrafas,
Hanne Hawle,
Gregoire Berthod,
Hermann S. Overkleeft,
Christiana Sessa,
Alwin Huitema,
Thomas Pabst,
Roger von Moos,
Dagmar Hess,
Ulrich J.M. Mey
Affiliations
Christoph Driessen
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Marianne Kraus
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Markus Joerger
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Hilde Rosing
Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
Jürgen Bader
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Felicitas Hitz
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Catherine Berset
SAKK Coordinating Center, Bern, Switzerland
Alexandros Xyrafas
SAKK Coordinating Center, Bern, Switzerland
Hanne Hawle
SAKK Coordinating Center, Bern, Switzerland
Gregoire Berthod
University Hospital CHUV, Lausanne, Switzerland
Hermann S. Overkleeft
University of Leiden, the Netherlands
Christiana Sessa
San Giovanni hospital, Bellinzona, Switzerland
Alwin Huitema
Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
Thomas Pabst
Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Switzerland
Roger von Moos
Hematology & Medical Oncology, Kantonsspital Graubuenden, Chur, Switzerland
Dagmar Hess
Department of Oncology/Hematology, Kantonsspital St. Gallen, Switzerland
Ulrich J.M. Mey
Hematology & Medical Oncology, Kantonsspital Graubuenden, Chur, Switzerland
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/m2, 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.