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Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.

ABSTRACT: KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.In this phase I, multicentre study, KW-2478 was administered intravenously over 1?h at doses ranging from 14 to 176?mg?m(-2) once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with ?2 regimens.There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of ?6?h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses ?71?mg?m(-2). Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for ?6 months.Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.

SUBMITTER: Yong K

PROVIDER: S-EPMC4716540 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.

Yong K K Cavet J J Johnson P P Morgan G G Williams C C Nakashima D D Akinaga S S Oakervee H H Cavenagh J J

British journal of cancer 20151222 1

<h4>Background</h4>KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.<h4>Methods</h4>In this phase I, multicentre study, KW-2478 was administered intravenously over 1 h at doses ranging from 14 to 176 mg m(-2) once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with ⩾2 regimens.<h4>Results</h4>There were ...[more]

PMID: 26695442

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Project description:BackgroundWith the widespread clinical application of tyrosine kinase inhibitors (TKIs), an increasing number of chronic myeloid leukaemia (CML) patients have developed resistance or intolerance to TKIs. BCR/ABL is the oncoprotein of CML. HSP90 is an essential chaperone of BCR/ABL and plays an important role in protein folding and the function of BCR/ABL. Therefore, inhibiting the chaperone function of HSP90 may be an effective strategy for CML treatment and to overcome TKI resistance.MethodsThe effect of KW-2478 on CML cell viability, apoptosis and cell cycle progression was detected by CCK-8 assay or flow cytometry. The levels of BCR/ABL, HSP90 and other signalling proteins were detected by western blots. The mitochondrial membrane potential was detected by flow cytometry combined with JC-1 staining. The interaction between BCR/ABL and HSP90α was detected by coimmunoprecipitation. The effect of KW-2478 on BCR/ABL carcinogenesis in vivo was investigated in CML-like mouse models.ResultsKW-2478 inhibited growth and induced apoptosis of CML cells. KW-2478 inhibited the chaperone function of HSP90α and then weakened the BCR/ABL and MAPK signalling pathways. This treatment also caused an increase in p27 and p21 expression and a decrease in cyclin B1 expression, which led to G2/M phase arrest. The mitochondrial pathway was primarily responsible for KW-2478-induced apoptosis. KW-2478 had a synergistic effect with imatinib in growth inhibition. Notably, KW-2478 had a stronger effect on growth inhibition, apoptosis induction and cell cycle arrest of K562/G01 cells than K562 cells. KW-2478 could effectively prolong the mouse lifespan and alleviate disease symptoms in CML-like mouse models.ConclusionsThis finding demonstrated that KW-2478 had anticancer properties in imatinib-sensitive and imatinib-resistant CML cells and illustrated the possible mechanisms. This study provides an alternative choice for CML treatment, especially for TKI-resistant patients with BCR/ABL amplification and TKI-intolerant patients.

Dataset Information

Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.

Publications

Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.

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