TY - JOUR
T1 - 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
T2 - A phase I trial (SAKK 65/08)
AU - Driessen, Christoph
AU - Kraus, Marianne
AU - Joerger, Markus
AU - Rosing, Hilde
AU - Bader, Jürgen
AU - Hitz, Felicitas
AU - Berset, Catherine
AU - Xyrafas, Alexandros
AU - Hawle, Hanne
AU - Berthod, Gregoire
AU - Overkleeft, Hermann S.
AU - Sessa, Christiana
AU - Huitema, Alwin
AU - Pabst, Thomas
AU - von Moos, Roger
AU - Hess, Dagmar
AU - Mey, Ulrich J.M.
N1 - Publisher Copyright:
© 2016 Ferrata Storti Foundation.
PY - 2016
Y1 - 2016
N2 - 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, bortezomibrefractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance (clinicaltrials.gov identifier: 01164709).
AB - 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, bortezomibrefractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance (clinicaltrials.gov identifier: 01164709).
UR - http://www.scopus.com/inward/record.url?scp=84959265657&partnerID=8YFLogxK
U2 - 10.3324/haematol.2015.135780
DO - 10.3324/haematol.2015.135780
M3 - Article
C2 - 26659919
AN - SCOPUS:84959265657
SN - 0390-6078
VL - 101
SP - 346
EP - 355
JO - Haematologica
JF - Haematologica
IS - 3
ER -