Targeting of RNA-binding protein FXR1 in HNSCC

HNSCC 中 RNA 结合蛋白 FXR1 的靶向

基本信息

批准号：
10571379
负责人：
Viswanathan Palanisamy
金额：
$ 41.94万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571379
关键词：
Ablation Affinity Amino Acids Animal Model Arginine Binding Biochemical Biological Assay Bypass CDKN1A gene Cancer Cell Growth Cell Aging Cells Chromosomes Clinical Trials Complex Data Development Drug Targeting Essential Amino Acids Essential Genes Event Evolution FDA approved FMR1 G-Quartets Gene Amplification Gene Expression Gene Silencing Genetic Glycine Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human In Vitro Intervention Ligands Lysine Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Mediating Messenger RNA Methods Methylation Methyltransferase MicroRNAs Modality Modeling Molecular Mouth Neoplasms Mutation Neoplasms Nuclear Export Nucleic Acids Oligonucleotides Oncogenic Oncoproteins Oral Pathway interactions Patients Pharmaceutical Preparations Play Post-Transcriptional Regulation Process Proliferating Proteins Proteomics Publishing RNA RNA Binding RNA Sequences RNA Stability RNA-Binding Proteins Radiolabeled Repression Role Signal Transduction Single-Stranded DNA Specificity Structure Survival Rate TP53 gene Telomerase RNA Component Testing Therapeutic Translations Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated RNA Work Xenograft procedure aptamer cancer cell cancer therapy cell growth demethylation design diagnostic value drug resistance development effective therapy efficacious treatment experimental study improved in vivo inhibitor innovation insight mRNA Transcript Degradation malignant mouth neoplasm metaplastic cell transformation mortality mouth squamous cell carcinoma mutant novel novel strategies novel therapeutic intervention novel therapeutics overexpression posttranscriptional pre-clinical prevent protein degradation recruit small molecule small molecule inhibitor telomere transcriptomics tumor tumor growth tumor progression tumorigenesis virtual

项目摘要

Abstract Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and accounts for more than 90% of head and neck cancers, with a 5-year survival rate of approximately 50%. Despite specific effective and novel therapies, most patients remain unresponsive to current treatment modalities and develop drug resistance. Therefore, identifying new molecules that target cancer pathways, alone or in combination, is critical for developing novel cancer therapies. In HNSCC, dysregulated RNA-binding proteins (RBPs) controls co- and post-transcriptional events. Approaches targeting RBPs are not well established to regulate the gene expression in cancers. Thus, new therapeutic strategies to control gene expression and tumor growth are necessary. Our published findings demonstrate that FXR1 directly binds the RNA G-quadruplex (G4) regions of mRNA CDKN1A and a non-coding RNA TERC (Telomerase RNA component) and promotes the growth and proliferation of HNSCC cells. Herein, our preliminary findings indicate that methylated arginine amino acids at the NES (nuclear export signal) and RGG (arginine-glycine rich) domain of FXR1 are responsible for G4-RNA binding and the growth of cancer cells. However, mutation of specific arginine residues in the NES/RGG domain abolished FXR1 binding with CDKN1A and TERC and reduced the growth and proliferation of oral cancer cells. Thus, targeting FXR1's RGG domain with specific inhibitors is considered an appealing drug target for oral cancer treatment. We plan to use nucleic acid-based aptamers that directly bind to the arginine amino acids present in NES/RGG domain of FXR1 and disrupt its RNA binding activities. Hence, the overall goal of this R21 proposal is to utilize structural and biochemical assays to screen and identify aptamers specific to the FXR1 NES/RGG domain to control its gene expression activities and the growth of oral cancer cells. Two specific aims are proposed to test this model. In specific aim1, we will determine how arginine methylation impacts FXR1 RNA- binding functions and oral tumor progression using in vitro RNA binding assays and in vivo tumor models. In specific aim2, we will develop an aptamer that directly binds and interfere with methylated FXR1-RNA complex and show anti-tumor activity in our preclinical animal models of HNSCC. Our present work is an innovative, straightforward, and robust approach to target the dysregulated RBP-mediated gene expression in HNSCC. We will use these mechanistic findings to develop novel strategies to treat aggressive HNSCC tumors.

抽象的头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，占 90%以上的头颈癌，5年生存率约为50%。尽管具体尽管有有效和新颖的疗法，但大多数患者对当前的治疗方式仍然没有反应，并发展为耐药性。因此，单独或组合识别靶向癌症途径的新分子是对于开发新型癌症疗法至关重要。在 HNSCC 中，失调的 RNA 结合蛋白 (RBP) 控制着共转录和转录后事件。针对 RBP 的基因调控方法尚未完善在癌症中的表达。因此，控制基因表达和肿瘤生长的新治疗策略是必要的。我们发表的研究结果表明 FXR1 直接结合 RNA G 四链体 (G4) 区域 mRNA CDKN1A 和非编码 RNA TERC（端粒酶 RNA 成分）并促进生长和 HNSCC 细胞增殖。在此，我们的初步研究结果表明，甲基化精氨酸氨基酸 FXR1 的 NES（核输出信号）和 RGG（富含精氨酸-甘氨酸）结构域负责 G4-RNA 结合和癌细胞的生长。然而，NES/RGG 结构域中特定精氨酸残基的突变废除 FXR1 与 CDKN1A 和 TERC 的结合，并减少口腔癌细胞的生长和增殖。因此，用特异性抑制剂靶向 FXR1 的 RGG 结构域被认为是口服药物的一个有吸引力的药物靶点。癌症治疗。我们计划使用直接与精氨酸结合的核酸适体存在于 FXR1 的 NES/RGG 结构域中并破坏其 RNA 结合活性。因此，R21的总体目标建议利用结构和生化分析来筛选和鉴定 FXR1 特异性适体 NES/RGG结构域控制其基因表达活性和口腔癌细胞的生长。两个具体目标建议测试该模型。在具体目标1中，我们将确定精氨酸甲基化如何影响 FXR1 RNA- 使用体外 RNA 结合测定和体内肿瘤模型研究结合功能和口腔肿瘤进展。在具体目标2，我们将开发一种适体，直接结合并干扰甲基化FXR1-RNA复合物并在我们的 HNSCC 临床前动物模型中显示出抗肿瘤活性。我们目前的工作是一项创新的、针对 HNSCC 中 RBP 介导的基因表达失调的简单而稳健的方法。我们将利用这些机制发现来开发治疗侵袭性 HNSCC 肿瘤的新策略。