Drugging EBNA1 to Treat EBV-Associated Cancers

药物 EBNA1 治疗 EBV 相关癌症

基本信息

批准号：
10430064
负责人：
Troy E Messick
金额：
$ 57.08万
依托单位：
WISTAR INSTITUTE
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：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430064
关键词：
Animal Model Antineoplastic Agents Apoptosis Automobile Driving Basic Science Binding Cell Proliferation Cell Survival Cell model Cells Chemicals Cisplatin Clustered Regularly Interspaced Short Palindromic Repeats DNA Binding DNA Binding Domain Data Development Disease Drug Design Elements Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm Fluorouracil Foundations Gene Expression Generations Genetic Genome Goals Growth Human Human Herpesvirus 4 Immune checkpoint inhibitor Investigation Latent virus infection phase Ligands Malignant Neoplasms Mediating Medical Modeling Modification Molecular Mus Nuclear Antigens Nuclear Protein Oncogenic Viruses Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Pharmacogenomics Proliferating Property Radiation Recording of previous events Reporting Resolvase Site Structure Testing Therapeutic Therapeutic Agents Translational Research Ubiquitin Viral Viral Genes Viral Genome Viral Proteins Virus Work anticancer activity base cancer therapy cancer type carcinogenesis cell growth cell type chemotherapeutic agent chemotherapy combinatorial endonuclease immune checkpoint immune function improved in vivo evaluation inhibitor insight latent infection multicatalytic endopeptidase complex neoplastic cell next generation novel therapeutic intervention novel therapeutics patient derived xenograft model programs recruit response small hairpin RNA small molecule small molecule inhibitor small molecule therapeutics standard of care targeted agent transcriptomics tumor tumor growth tumorigenesis ubiquitin-protein ligase virus related cancer

项目摘要

Project Summary EBV latent infection is responsible for ~200,000 new cancers per year. To date, there are no EBV- specific therapeutic agents that selectively and efficaciously treat EBV-positive tumors. All known EBV tumors consistently express one viral nuclear protein, EBNA1, that is required for maintaining the EBV genome and promoting infected cell survival. We have developed highly selective, drug-like small molecules that bind EBNA1 and block its ability to bind DNA, maintain EBV genomes, and promote host-cell survival. Here we propose to better understand the mechanism through which disruption of EBNA1 DNA binding leads to tumor growth inhibition, and use this information to identify rational combinatorial agents to enhance chemotherapeutic efficacy. We propose to enhance the potency of the first generation EBNA1 inhibitors by attaching proteasome targeting molecules (PROTACS) to selectively target EBNA1 for degradation. Finally, we will take advantage of new mechanistic data revealing that EBNA1 functions as an OriP-specific endonuclease and resolvase. We propose to develop new structure and mechanism-based inhibitors of EBNA1 that can increase potency necessary for highly efficacious cancer therapy. By integrating these strategies to understand the growth arrest response of EBNA1 inhibition (aim 1) to better develop rational approaches for combinatorial therapies (aim 2) and develop next generation molecule with structure/mechanism based drug design principles (aim 3), we will advance EBNA1 inhibitors for the treatment of EBV-associated malignancies and related-diseases. We will test the overarching hypothesis that EBNA1 is an effective target for small molecule inhibitors to treat EBV cancers. The major goal of this proposal is to understand the tumor cell response to EBNA1 inhibition and to enhance efficacy of EBNA1 inhibitors to treat EBV-associated cancers more efficaciously. The team associated with this proposal has the unique expertise and strong collaborative history to execute the aims of this proposal. Collectively, these investigations will provide fundamental insights into how EBNA1 functions at the molecular level and will lay the foundation for the development of new strategies to treat EBV cancers.

项目概要 EBV 潜伏感染每年导致约 200,000 例新发癌症。迄今为止，还没有 EBV- 选择性和有效治疗 EBV 阳性肿瘤的特异性治疗剂。众所周知 EBV 肿瘤始终表达一种病毒核蛋白 EBNA1，这是维持 EBV 基因组并促进感染细胞存活。我们开发了高度选择性的类药物结合 EBNA1 并阻断其结合 DNA 的能力、维持 EBV 基因组的小分子，以及促进宿主细胞的存活。在这里，我们建议更好地理解这一机制 EBNA1 DNA 结合的破坏会导致肿瘤生长抑制，并使用此信息来识别合理联合用药，提高化疗疗效。我们建议加强通过连接蛋白酶体靶向分子来确定第一代 EBNA1 抑制剂的效力 (PROTACS) 选择性地靶向 EBNA1 进行降解。最后，我们将利用新的机制数据表明 EBNA1 作为 OriP 特异性核酸内切酶和解离酶发挥作用。我们建议开发基于新结构和机制的 EBNA1 抑制剂，可以增加高效癌症治疗所需的效力。通过将这些策略整合到了解 EBNA1 抑制的生长停滞反应（目标 1），以更好地开发合理的组合疗法（目标 2）的方法并开发下一代分子基于结构/机制的药物设计原则（目标 3），我们将推进 EBNA1 抑制剂 EBV 相关恶性肿瘤和相关疾病的治疗。我们将测试总体假设 EBNA1 是小分子抑制剂治疗 EBV 的有效靶点癌症。该提案的主要目标是了解肿瘤细胞对 EBNA1 的反应抑制并增强 EBNA1 抑制剂治疗 EBV 相关癌症的功效有效地。与此提案相关的团队拥有独特的专业知识和强大的实力执行本提案目标的合作历史。总的来说，这些调查将提供关于 EBNA1 如何在分子水平发挥作用的基本见解，并将奠定为开发治疗 EBV 癌症的新策略奠定了基础。