Regulation of non-proteolytic ubiquitination in cancer chemoresistance and progression

非蛋白水解泛素化在癌症化疗耐药和进展中的调节

基本信息

批准号：
10407385
负责人：
Erik Knudsen
金额：
$ 38.48万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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：
2017-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407385
关键词：
Adjuvant Therapy Affect Animals Biochemical Biological Biological Assay Biological Markers Cell Count Cell Nucleus Cells Chemoresistance Clinical Trials Cytotoxic Chemotherapy DNA Repair Data Development Disease Down-Regulation Drug Targeting Epithelial Exhibits Flow Cytometry Goals Head and Neck Cancer Histologic Human In Vitro Incidence Individual Knowledge Link Lysine Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mammospheres Measures Mediating Mesenchymal Molecular Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Oncogenic Outcome Pathologic Pathway interactions Patients Phenotype Physiological Pluripotent Stem Cells Polyubiquitin Prognostic Marker Property Proteins Public Health Publishing Regulation Relapse Risk Factors Role Scheme Series Signal Pathway Signal Transduction Specificity Subgroup TWIST1 gene Testing The Cancer Genome Atlas Therapeutic Tissues Transgenic Mice Transplantation Ubiquitin Ubiquitination Work Xenograft procedure anti-cancer base breast cancer progression cancer cell cancer stem cell cancer subtypes chemotherapy combat epithelial to mesenchymal transition genetic profiling in vivo inhibitor/antagonist malignant breast neoplasm mortality mouse model mutant new therapeutic target novel novel strategies overexpression personalized medicine predicting response protein degradation protein expression self-renewal stem stem cell expansion stem cell self renewal stemness success therapeutically effective therapy resistant transcription factor treatment response triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary Triple-negative breast cancer (TNBC) is a group of aggressive diseases with a greater incidence of relapse, metastasis and patient mortality compared to other breast cancer subtypes. Genetic profiling studies have identified at least six subgroups of TNBC exhibiting distinct molecular features. These subgroup- associated molecular features, or ‘biomarkers’, may eventually be used to predict response to treatment; however, not all biomarkers cause tumor progression and/or treatment resistance. It is therefore critical to better understand the molecular drivers that underlie TNBC subgroups. TNBC expresses abundant Twist, a fundamental and versatile regulator of TNBC progression. Despite being a long-standing drug target, there is no approach to specifically target Twist activity. Ubiquitin is an important regulatory signal. K48-linked ubiquitination causes degradation and downregulation of protein substrates, whereas the newly characterized K63-linked ubiquitination activates protein-mediated signaling pathways. E3 ligases are the substrate recognition protein that impart specificity to the ubiquitin signal. Many E3 ligases are upregulated in human cancers. Several inhibitors that inactivate the oncogenic E3 ligases are currently being tested in clinical trials. By identifying which E3 ligases account for the K63-linked ubiquitination of Twist, we could potentially discover new drug targets that specifically block Twist to treat TNBC. The goal of this application is to characterize the K63-linked ubiquitination network that orchestrates Twist activation and protein expression and to identify the E3 ligases responsible for Twist K63-linked ubiquitination. We will conduct a series of biochemical and biological studies to uncover the mechanisms by which K63-linked ubiquitination regulates Twist activity post-translationally. We will establish the pathological roles of Twist K63-linked ubiquitination and its controlling E3 ligases in animal studies. We will validate the physiological relevance of E3 ligases as functional biomarkers in TNBC tumors and assess whether inhibiting these E3 ligases has therapeutic potential. Relevance to Public Health: Our study characterizing E3 ligases as molecular drivers of TNBC will open the door to developing new strategies for effectively treating TNBC. Through a non-biased E3 ligase screen, we identified two primary Twist-controlling E3 ligases that appear to be present in most TNBC tissues in a mutually exclusive fashion, most likely as the result of tumor heterogeneity. If the two E3 ligases, individually or in combination, do affect TNBC regulation, then they could be used as functional prognosis markers in personalized medicine. Aside from TNBC, the knowledge gained through this work is potentially applicable to other tumor types where Twist activation is implicated, such as prostrate, lung, head and neck cancers.

项目摘要三阴性乳腺癌（TNBC）是一组侵略性疾病与其他乳腺癌亚型相比，复发，转移和患者死亡率。基因分析研究已经确定了至少六个具有不同分子特征的TNBC亚组。这些亚组 - 相关的分子特征或“生物标志物”有时可以用来预测对治疗的反应；但是，并非所有生物标志物都会引起肿瘤进展和/或治疗耐药性。因此，至关重要更好地了解TNBC亚组的分子驱动因素。 TNBC表达了丰富的扭曲，这是TNBC进展的基本和多功能调节剂。尽管作为长期存在的药物靶标，没有方法可以专门针对扭曲活动。泛素是一个重要的调节信号。 K48连接的泛素化会导致蛋白质降解和下调底物，而新表征的K63连接的泛素化激活了蛋白质介导的信号传导途径。 E3连接酶是对泛素信号赋予特异性的底物识别蛋白。许多 E3连接酶在人类癌症中被上调。几种使致癌E3连接酶失活的抑制剂是目前正在临床试验中进行测试。通过识别哪些E3连接酶解释了K63连接的泛素化扭曲，我们可能会发现新的药物靶标，这些靶标特异性地阻断了治疗TNBC的扭曲。该应用程序的目的是表征协调的K63连接的泛素化网络扭曲激活和蛋白质表达，并确定负责扭曲K63连接的E3连接酶泛素化。我们将进行一系列生化和生物学研究，以发现通过 K63连接的泛素化在翻译后调节扭曲活动。我们将建立病理扭曲K63连接的泛素化的作用及其在动物研究中控制的E3连接酶。我们将验证 E3连接酶是TNBC肿瘤中功能生物标志物的生理相关性，并评估是否抑制这些E3连接酶具有治疗潜力。与公共卫生相关：我们的研究表征了E3连接酶由于TNBC的分子驱动因素将为开发有效治疗TNBC的新策略打开大门。通过无偏置的E3连接酶屏幕，我们确定了两个主要的扭曲控制E3连接酶以互斥的方式存在于大多数TNBC组织中，很可能是由于肿瘤的结果异质性。如果两个单独或组合的两个E3连接酶确实会影响TNBC调节，那么他们可以用作个性化医学中的功能预后标记。除了TNBC，知识还获得了通过这项工作，可能适用于实施扭曲激活的其他肿瘤类型，例如俯卧，肺，头颈癌。