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：
9767082
负责人：
Mei Yee Koh
金额：
$ 32.68万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767082
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）是肾癌最常见和侵略性的形式是对治疗的最具耐药性。 Hippel Lindau（VHL）肿瘤抑制基因，导致低氧诱导的构成激活 HIF-1α和HIF-2α的因素是由HIF-2α驱动的因此，HIF-2α的抑制作用是CCRC的吸引力。筛选运动，我们已经确定了一系列章节降低HIF-2α蛋白和没有亲密的HIF-1α的活动。在HIF-2α的5'未翻译区域内的铁响应元件（IRE）的调节蛋白（IRP）-1 mRNA，抑制HIF-2α的翻译。簇组件2（ISCA2）作为这些化合物的分子靶标铁硫簇进入IRP-1，该簇调节其刺激作用。由缺氧诱导，是推定的PVHL靶标，表明ISCA2可能发挥缺氧或CCRCC- 具体作用。正常肾脏，并显着相关。没有亲密的HIF-1α，并且无独立于HIF-2α耗尽细胞铁。小分子抑制CCRCCCCC异种移植的生长，并降低肿瘤内HIF-2α蛋白假设是“ ISCA2在促进驱动HIF-2α和细胞铁中起着核心作用” CCRCC的进展。 2α和细胞铁的部署用于治疗CCRCC”。介导缺氧的ISCA2指示； CCRC中的代谢是研究ISCA2调制的影响使用体外和体内模型进行进展，并确定使用临床的生理相关性人CCRC的样品（来自600名患者的样本）。 ISCA2吸收对HIF-2α和细胞质铁的治疗影响，探索是治疗我们研究的总体目标是确定ISCA2，HIF-2α和Thee的机制铁代谢的放松管制有助于CRCC的进步。将为CCRCC患者产生不良治疗益处。