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A novel approach for the selective inhibition of HIF-2a in kidney cancer

选择性抑制肾癌中 HIF-2a 的新方法

基本信息

批准号：
10227021
负责人：
Mei Yee Koh
金额：
$ 33.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227021
关键词：
5&apos Untranslated Regions Affect Automobile Driving Binding Clear Cell Clear cell renal cell carcinoma Clinical Disease Drug resistance Elements Etiology Genes Genetic Genetic Transcription Goals Growth Heterodimerization Human Hypoxia Hypoxia Inducible Factor In Vitro Iron Iron Chelating Agents Iron Regulatory Protein 1 KRAS2 gene Kidney Link Mediating Medical Messenger RNA Metabolism Molecular Target Mutation Neoplasm Metastasis Oral Patients Physiological Play Production Proteins Proteomics Regulation Renal Cell Carcinoma Renal carcinoma Resistance Role Sampling Series Solid Neoplasm Sulfur TP53 gene Therapeutic Tissues Translations Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft procedure advanced disease angiogenesis base cancer cell cancer therapy cell type checkpoint inhibition clinically relevant high throughput screening in vivo in vivo Model inhibitor/antagonist iron metabolism novel strategies response small molecule small molecule inhibitor targeted agent therapeutic target treatment response tumor tumor growth tumor progression uptake

项目摘要

Clear cell type renal cell carcinoma (CCRCC) is the most common and aggressive form of kidney cancer, and is among the most resistant of solid tumors to therapy. CCRCC is typically initiated by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene, resulting in the constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. CCRCC progression is uniquely driven by HIF-2α, whereas HIF-1α plays a tumor suppressor role. Thus, HIF-2α is an attractive therapeutic target for CCRCC. Through a high throughput screening campaign, we have identified a series of compounds that selectively decrease HIF-2α protein and activity without affecting HIF-1α. We show that these compounds act by enhancing the binding of iron regulatory protein (IRP)-1 to the iron-responsive element (IRE) within the 5' untranslated region of HIF-2α mRNA, which inhibits HIF-2α translation. Using an unbiased global proteomic screen, we confirm Iron-sulfur Cluster Assembly 2 (ISCA2) as the molecular target of these compounds. ISCA2 regulates the incorporation of the iron-sulfur cluster into IRP-1, which modulates its IRE-binding activity. ISCA2 is non-transcriptionally induced by hypoxia, and is a putative pVHL target, suggesting that ISCA2 may play a hypoxia- or CCRCC- specific role. We observe that both ISCA2 and cellular iron are upregulated in CCRCC compared to paired normal kidney, and are significantly correlated. Inhibition of ISCA2 selectively decreases HIF-2α protein without affecting HIF-1α, and depletes cellular iron independently of HIF-2α. Significantly, ISCA2 inhibition by small molecules inhibits CCRCC xenograft growth, and decreases intra-tumoral HIF-2α protein. Thus, our hypothesis is that “ISCA2 plays a central role in promoting the elevation of HIF-2α and cellular iron that drive CCRCC progression. Hence, the targeting of ISCA2 provides a novel strategy for the specific inhibition of HIF- 2α and depletion of cellular iron for the treatment of CCRCC”. Our first aim is to identify the mechanisms mediating ISCA2 induction in hypoxia; and to characterize its role in the regulation of HIF-2α and iron metabolism in CCRCC. Our second aim is to investigate the impact of ISCA2 modulation on CCRCC progression using in vitro and in vivo models, and to determine its physiological relevance using clinical samples of human CCRCC (samples from 600 patients obtained). Our third aim is to investigate the therapeutic impact of ISCA2 inhibition on HIF-2α and cytoplasmic iron, and to explore its use for the treatment of CCRCC. The overall goal of our studies is to identify the mechanisms by which ISCA2, HIF-2α and the deregulation of iron metabolism contribute to CRCC progression; and to determine whether ISCA2 inhibition will yield increased therapeutic benefit for patients with CCRCC.

透明细胞型肾细胞癌（CCRCC）是肾癌的最常见和侵袭性形式，是对治疗最有抵抗力的实体瘤之一。CCRCC通常由血管内皮细胞的失活启动。 Hippel Lindau（VHL）肿瘤抑制基因，导致缺氧诱导的因子：HIF-1α和HIF-2α。CCRCC的进展是由HIF-2α独特驱动的，而HIF-1α在CCRCC的发展中起着重要作用。抑制作用。因此，HIF-2α是CCRCC有吸引力的治疗靶点。通过高吞吐量筛选活动中，我们已经确定了一系列选择性降低HIF-2α蛋白的化合物，而不影响HIF-1α。我们发现这些化合物通过增强铁的结合作用 HIF-2α 5'端非翻译区的铁反应元件（IRE）调控蛋白（IRP）-1 抑制HIF-2α翻译的mRNA。使用公正的全球蛋白质组学筛选，我们确认铁硫簇组装体2（ISCA 2）作为这些化合物的分子靶标。ISCA 2规定，铁硫簇合物转化为IRP-1，从而调节其IRE结合活性。ISCA 2是非转录的诱导的缺氧，是一个假定的pVHL的目标，这表明ISCA 2可能发挥缺氧-或CCRCC- 具体角色。我们观察到，与配对相比，CCRCC中ISCA 2和细胞铁均上调正常肾脏，并有显着相关性。抑制ISCA 2选择性降低HIF-2α蛋白而不影响HIF-1α，并独立于HIF-2α消耗细胞铁。值得注意的是，ISCA 2抑制小分子抑制CCRCC异种移植物生长，并降低肿瘤内HIF-2α蛋白。所以我们假设是“ISCA 2在促进HIF-2α和细胞铁的升高中起着核心作用， CCRCC进展。因此，靶向ISCA 2为特异性抑制HIF-1 α提供了一种新的策略。 2α和细胞铁耗竭治疗CCRCC”。我们的首要目标是确定在缺氧条件下介导ISCA 2的诱导;并表征其在调节HIF-2α和铁 CCRCC中的代谢。我们的第二个目标是研究ISCA 2调节对CCRCC的影响。使用体外和体内模型，并使用临床试验确定其生理相关性人CCRCC样本（获得600名患者的样本）。我们的第三个目标是调查 ISCA 2抑制对HIF-2α和细胞质铁的治疗影响，并探索其用于治疗关于CCRCC我们研究的总体目标是确定ISCA 2、HIF-2α和HIF-1 α在肿瘤发生中的作用机制。铁代谢的失调有助于CRCC进展;并确定ISCA 2抑制是否将增加CCRCC患者的治疗获益。