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Anti-cancer therapeutic approaches for targeting the ALT telomere maintenance mechanism

针对 ALT 端粒维持机制的抗癌治疗方法

基本信息

批准号：
10683151
负责人：
Jaewon Min
金额：
$ 19.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683151
关键词：
3-Dimensional ATP phosphohydrolase Acute Promyelocytic Leukemia Alternative Therapies Applications Grants Biological Assay Biophysics Biotinylation CRISPR screen Cancer cell line Candidate Disease Gene Cell Culture System Cell Culture Techniques Cell Line Cells Cellular biology Clinical Trials Cluster Analysis Complementary DNA DNA Repair Pathway DNA biosynthesis Diagnosis Endocrine Gland Neoplasms Engineering Fluorescent in Situ Hybridization Future Gel Generations Genes Glioblastoma Glioma Goals Human K22 Award Malignant Childhood Neoplasm Malignant Neoplasms Mediating Mesenchymal Mitotic Modeling Molecular Molecular Chaperones Molecular Target Neuroblastoma Normal tissue morphology Patients Phase Phenotype Physical condensation Polymerase Positioning Attribute Post-Translational Protein Processing Process Proliferating Proteins Proteome Proteomics Publications Publishing Reaction Research Research Institute Research Personnel Series Sumoylation Pathway Suppressor Genes System Techniques Telomerase Telomerase inhibition Telomere Maintenance Telomere Pathway Testing Therapeutic Toxic effect Training Ubiquitin Ubiquitination United States Universities Work Xenograft Model Xenograft procedure alternative treatment anti-cancer therapeutic cancer cell career early childhood experimental study genome wide screen genome-wide genome-wide analysis improved in vivo molecular targeted therapies mutant new therapeutic target novel novel therapeutics osteosarcoma overexpression patient derived xenograft model personalized cancer therapy professor reconstitution sarcoma scaffold screening segregation small hairpin RNA small molecule inhibitor stable cell line stem-like cell subcutaneous telomere therapeutic target tumor tumor DNA tumor growth tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary/Abstract During tumorigenesis, cancer cells need to acquire a telomere maintenance mechanism to proliferate indefinitely. Cancers of mesenchymal origin (such as sarcomas, endocrine tumors, glioblastoma, and some early childhood cancers), frequently acquire a telomerase-independent telomere maintenance mechanism, which has been termed Alternative Lengthening of Telomeres (ALT). Moreover, it has been shown that telomerase inhibition in telomerase positive human cancer cells can engage the ALT pathway. Although ALT cancers can be diagnosed by telomere fluorescence in situ hybridization (FISH) of tumor sections, and by using the C-circle assay (phi29 polymerase reaction) of tumor DNA, currently there are no therapeutic targets or clinical trials for ALT tumor treatment. Therefore, identification of potential therapeutic targets for ALT tumors may significantly improve the options for patients with ALT cancers by identifying and exploitering unique ALT cancer vulnerabilities. Ultimately, this should lead to personalized cancer treatment based on ALT status. From my recent studies, I found that the molecular mechanism of ALT is initiated by excessive and persistent clustering of telomeres in PML bodies. I have been further investigating that these processes are mediated by a series of post-translational modifications and segregation: ubiquitination by SUMO-targeted ubiquitination E3 ligase (RNF4), and segregation by ubiquitin- selective chaperone/AAA ATPase (p97; also known as VCP). In aim 1, I will further dissect the mechanism of RNF4 and p97 in ALT pathway and validate the therapeutic window of opportunity to inhibit the RNF4-p97 axis as an effective anti-ALT cancer strategy. One of the hallmarks of ALT cancers is the clustering of large amounts of telomeres in promyelocytic leukemia (PML) bodies. I have developed a biophysical system that reconstitutes PML bodies from minimal components and generates telomere clustering, thus mimicking ALT-associated PML bodies (APBs) in vivo. In aim 2, I will further engineer the biophysical system mimicking ALT cancer phenotype and apply this ALT model to proteomics and candidate gene screenings to identify novel therapeutic targets for ALT cancer. My primary career goal is to obtain an assistant professor position at a R1 university or research institute in the United States. My long-term career goal is to become an independent investigator and leader in the field of cancer cell biology. Training under a K22 award will serve as the basis for the future direction of my research, and the resulting publications will support my transition toward independence and prepare me to submit additional grant applications including R01s. The results that I obtain from Aim 1 and Aim 2 will allow me to further investigate the molecular mechanisms of the ALT pathway to identify new molecular targets and novel therapies for ALT cancers that are not currently available.

项目总结/摘要在肿瘤发生期间，癌细胞需要获得端粒维持机制以无限增殖。间质起源的癌症（如肉瘤、内分泌肿瘤、胶质母细胞瘤和一些儿童早期肿瘤）癌症），经常获得一个端粒不依赖端粒维持机制，这已经被端粒替代延长（ALT）此外，已经表明，端粒酶抑制在肿瘤细胞中起重要作用。端粒酶阳性的人癌细胞可以参与ALT途径。虽然ALT癌症可以被诊断为通过肿瘤切片的端粒荧光原位杂交（FISH），以及通过使用C环测定（phi 29 虽然目前还没有针对ALT肿瘤的治疗靶点或临床试验，治疗因此，鉴定ALT肿瘤的潜在治疗靶点可以显著改善ALT肿瘤的治疗效果。通过识别和利用独特的ALT癌症脆弱性，为ALT癌症患者提供选择。最后，这将导致基于ALT状态的个性化癌症治疗。从我最近的研究中，我发现 ALT的分子机制是由PML小体中端粒的过度和持续聚集引发的。我我一直在进一步研究这些过程是由一系列翻译后修饰介导的和分离：通过SUMO靶向泛素化E3连接酶（RNF 4）的泛素化，和通过泛素- 选择性伴侣/AAA ATP酶（p97;也称为VCP）。在目标1中，我将进一步剖析 RNF 4和p97在ALT途径中的作用，并验证抑制RNF 4-p97轴的治疗机会窗作为有效的抗ALT癌症策略。ALT癌症的特征之一是大量的端粒在早幼粒细胞白血病（PML）机构。我开发了一个生物物理系统 PML体从最小的组成部分，并产生端粒聚类，从而模仿ALT相关的PML 体内的APBs。在目标2中，我将进一步设计模拟ALT癌症表型的生物物理系统并将此ALT模型应用于蛋白质组学和候选基因筛选，以确定新的治疗靶点， ALT癌我的主要职业目标是在R1大学或研究机构获得助理教授职位在美国的研究所。我的长期职业目标是成为一名独立调查员和领导者，癌症细胞生物学领域。K22奖项下的培训将作为我未来发展方向的基础。研究，以及由此产生的出版物将支持我向独立的过渡，并准备我，提交额外的赠款申请，包括R 01。我从目标1和目标2中得到的结果将允许我进一步研究ALT途径的分子机制，以确定新的分子靶点和新的 ALT癌症的治疗目前还没有。