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)
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)
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DOI：
10.3324/haematol.2015.135780
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发表时间：
2016-03-01
期刊：
影响因子：
10.1
通讯作者：
Mey, Ulrich J. M.
中科院分区：
文献类型：
--
作者：
Driessen, Christoph;Kraus, Marianne;Mey, Ulrich J. M.
未折叠蛋白反应的下调介导了多发性骨髓瘤中蛋白酶体抑制剂的耐药性。人免疫缺陷病毒蛋白酶抑制剂奈非那韦在体外激活未折叠蛋白反应。我们确定了奈非那韦与蛋白酶体抑制剂硼替佐米联合使用的剂量限制性毒性和推荐剂量。12例晚期血液系统恶性肿瘤患者接受奈非那韦（2500- 5000mg /天，p.o，第114天，3+3剂量递增）和硼替佐米(1.3 mg/m(2)，第1,4,8,11天；21天的周期)。奈非那韦单药治疗的一期试验允许在存在或不存在硼替佐米的情况下对奈非那韦进行药代动力学/药效学评估。终点包括剂量限制性毒性、未折叠蛋白反应的激活、蛋白酶体活性、毒性和对试验治疗的反应。奈非那韦2x2500mg是推荐的II期剂量。奈非那韦可显著上调外周血单核细胞中未折叠蛋白反应相关蛋白的表达，抑制蛋白酶体活性。在剂量递增队列的10名可评估患者中，3名获得部分缓解，4名病情稳定2个周期或更长时间，而3名病情进展为最佳缓解。在一项探索性扩展队列研究中，6名复发、硼替佐米难治、来那度胺耐药的骨髓瘤患者接受了推荐的II期剂量治疗，其中3人达到部分缓解，2人达到轻微缓解，1人病情进展。奈非那韦联合硼替佐米是安全的，并且在晚期硼替佐米难治性多发性骨髓瘤中显示出有希望的活性。奈非那韦诱导未折叠蛋白反应可能克服蛋白酶体抑制剂耐药的生物学特性（临床试验）。Gov标识符：01164709)。
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 114, 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 2x2500 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).