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Drugging EBNA1 to Treat EBV-Associated Cancers

药物 EBNA1 治疗 EBV 相关癌症

基本信息

批准号：
10185459
负责人：
PAUL M LIEBERMAN
金额：
$ 58.25万
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/10185459
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/antagonist 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.

项目总结