An update on the status of HSP90 inhibitors in cancer clinical trials

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Shraddha Rastogi , Abhinav Joshi , Nahoko Sato , Sunmin Lee , Min-Jung Lee , Jane B. Trepel , Len Neckers
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引用次数: 0

Abstract

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

HSP90 抑制剂在癌症临床试验中的最新进展。
进化保守的分子伴侣 HSP90 通过稳定客户癌蛋白,在肿瘤发生过程中发挥着不可或缺的作用。虽然 HSP90 的功能受到严格调控,但癌细胞对这种伴侣蛋白表现出独特的依赖性,导致其过度表达,这与某些恶性肿瘤的不良预后有关。虽然针对与致癌有关的热休克蛋白的各种策略已被探索过,但只有抑制 HSP90 才能持续有效地导致其客户蛋白的蛋白酶体降解。根据 clinicaltrials.gov 的报告,迄今为止,共有 22 种 HSP90 抑制剂在 186 项癌症临床试验中接受了测试。在这些试验中,60%已经完成,10%正在进行中,30%已经暂停、终止或撤销。在临床试验中,HSP90 抑制剂被用作单药或与其他药物联用治疗各种癌症类型。值得注意的是,由于 HSP90 抑制剂具有协同抗肿瘤作用,因此在联合疗法中使用 HSP90 抑制剂可改善临床疗效。然而,作为单药,HSP90 抑制剂因药物相关毒性或耐药性而显示出有限的临床活性。最近,日本对 TAS-116(pimitespib)进行了积极的试验评估,结果表明该药作为单药或与免疫检查点抑制剂 nivolumab 联用时毒性低,前景看好。各种试验中进行的探索性生物标志物分析表明,靶点参与表明有可能识别出对疗法有良好反应的患者群体。在本综述中,我们将讨论过去五年中有关 HSP90 抑制剂的研究进展及其对抗癌疗法的影响。我们的重点在于评估药物疗效、预后预测、药效生物标志物以及已发表试验报告的临床结果。通过这篇全面的综述,我们希望阐明 HSP90 抑制剂在癌症治疗中的进展和潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Stress & Chaperones
Cell Stress & Chaperones 生物-细胞生物学
CiteScore
7.60
自引率
2.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.
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