Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.
Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.
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DOI：
10.1126/scitranslmed.abb5647
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发表时间：
2020-12-16
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
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作者：
热休克因子1（HSF1）是一种细胞应激保护性转录因子，被广泛的癌症所利用，以驱动增殖、存活、侵袭和转移。核HSF1丰度是癌症严重程度、治疗抗性和缩短患者生存期的预后指标。在这里，我们证明了HSF1基因被扩增，并且在前列腺癌中，特别是在没有可用治疗选择的神经内分泌前列腺癌（NEPC）患者中，核HSF1丰度显著升高。尽管HSF1作为一系列癌症的治疗靶点的基因验证，但直接和选择性的小分子HSF1抑制剂尚未被验证或开发用于临床。我们提出了一种直接的HSF 1抑制剂，直接靶向HSF 1抑制剂（DTHIB），它物理地接合HSF 1并选择性地刺激核HSF 1降解。DTHIB强烈抑制HSF 1癌症基因签名和前列腺癌细胞增殖。DTHIB在四种治疗抗性前列腺癌动物模型中有效地减弱肿瘤进展，包括在NEPC模型中显著增强肿瘤消退。这项研究报告了直接HSF1抑制剂的鉴定和验证，并为前列腺癌和其他耐药癌症的小分子HSF1靶向治疗的开发提供了一条前进的道路。HSF 1的直接小分子抑制剂在治疗抗性前列腺癌的动物模型中引起显著的肿瘤消退。
Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is prognostic for cancer severity, therapy-resistance, and shortened patient survival. Here we demonstrated that the HSF1 gene was amplified, and nuclear HSF1 abundance was dramatically elevated in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC) patients, who have no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We presented the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates nuclear HSF1 degradation. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. DTHIB potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including the profound potentiation of tumor regression in a NEPC model. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path forward for the development of a small molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers. A direct small molecule inhibitor of HSF1 causes profound tumor regression in animal models of therapy-resistant prostate cancer.
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影响因子：
16.6
作者：
Gomez-Pastor R;Burchfiel ET;Neef DW;Jaeger AM;Cabiscol E;McKinstry SU;Doss A;Aballay A;Lo DC;Akimov SS;Ross CA;Eroglu C;Thiele DJ
通讯作者：
Thiele DJ
影响因子：
64.5
作者：
Dai, Chengkai;Whitesell, Luke;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
7.2
作者：
Joutsen, Jenny;Sistonen, Lea
通讯作者：
Sistonen, Lea
DOI：
10.1007/978-1-4939-7477-1_1
发表时间：
2018-01-01
期刊：
CHAPERONES
影响因子：
--
作者：
Jin, Xiongjie;Eroglu, Binnur;Mivechi, Nahid F.
通讯作者：
Mivechi, Nahid F.
影响因子：
16.8
作者：
Jaeger AM;Pemble CW 4th;Sistonen L;Thiele DJ
通讯作者：
Thiele DJ