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.

项目摘要 EBV潜在感染每年造成约20万次新癌症。迄今为止，没有EBV- 特定的治疗剂，可有选择地治疗EBV阳性肿瘤。都是已知的 EBV肿瘤始终表达一种病毒核蛋白EBNA1，这是维持所必需的 EBV基因组并促进感染的细胞存活。我们已经开发了高度选择性，类似药物样结合EBNA1并阻止其结合DNA，维持EBV基因组和的小分子促进宿主细胞生存。在这里，我们建议更好地了解 EBNA1 DNA结合的破坏会导致肿瘤生长抑制，并使用此信息识别合理组合剂以增强化学治疗功效。我们建议增强通过连接蛋白酶体靶向分子，第一代EBNA1抑制剂的效力（PROTAC）选择性靶向EBNA1进行降解。最后，我们将利用新的优势机械数据表明，EBNA1充当特异性的内切酶和分辨率。我们建议开发基于EBNA1的新结构和基于机制的抑制剂高效癌症治疗所需的效力。通过将这些策略整合到了解EBNA1抑制的生长停滞响应（AIM 1）以更好地发展理性组合疗法的方法（AIM 2），并使用基于结构/机制的药物设计原理（AIM 3），我们将推进EBNA1抑制剂治疗与EBV相关的恶性肿瘤和相关疾病。我们将测试总体假设EBNA1是小分子抑制剂治疗EBV的有效靶标癌症。该提案的主要目的是了解肿瘤细胞对EBNA1的反应抑制和增强EBNA1抑制剂治疗EBV相关癌症的功效有效。与该建议相关的团队具有独特的专业知识和强大协作历史记录以执行该提案的目标。这些调查总共提供有关EBNA1在分子水平上的功能的基本见解，并将放置制定新策略来治疗EBV癌症的基础。