权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Synthetic Lethal Targeting of CREBBP/EP300 in Head and Neck Squamous Cell Carcinoma

CREBBP/EP300 在头颈鳞状细胞癌中的合成致死靶向

基本信息

批准号：
10804966
负责人：
Curtis Pickering
金额：
$ 56.38万
依托单位：
YALE UNIVERSITY
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：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10804966
关键词：
Acetyltransferase Aerodigestive Tract Apoptotic Binding Biological Markers Bromodomain CREBBP gene Cell Death Cell Line Cells Cessation of life Chemicals Chromatin Clinic Clinical Clinical Trials DNA Damage DNA Repair DNA Sequence Alteration Data Dose EP300 gene Genes Genetic Transcription Genomics Global Change Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Histone Acetylation In Vitro Knock-out Link Measures Mediating Mutate Mutation Oncogenic Outcome PLK1 gene Pathway interactions Patient Care Patients Pattern Pharmaceutical Preparations Phenotype Platinum Pre-Clinical Model Protein Acetylation Proteins Radiation Radiation therapy Role Schedule Site Testing Therapeutic Therapeutic Agents Toxic effect Translating Translations Treatment Failure Tumor Suppressor Genes Tumor-Suppressor Gene Inactivation advanced disease candidate marker cell type comparative cytotoxic cytotoxicity dosage experimental study functional genomics genomic biomarker histone acetyltransferase improved in vivo in vivo evaluation inhibitor knock-down mutant new therapeutic target novel preclinical study radiation response response response biomarker side effect small molecule targeted agent targeted biomarker targeted treatment therapeutic target tumor

项目摘要

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors from the upper aerodigestive tract with relatively poor outcomes and limited targeted therapeutic options. Most patients are treated with a combination of DNA damaging agents (platinum, XRT). Recent genomic characterization of these tumors has not identified targetable oncogenic drivers, thus emphasizing the need to develop rational genomic-based approaches to increase sensitivity to treatments that induce DNA damage. We performed an in vivo functional genomic screen in genomically characterized HNSCC cell lines alone or in combination with DNA damaging agents. Knock-down of CREBBP or EP300 was identified as a potential mechanism to sensitize cells to the DNA damage response. CREBBP and EP300 are homologous multifunctional bromodomain-containing acetyltransferases that can regulate many proteins and pathways. Importantly, CREBBP and EP300 are mutated in 13% of HNSCC and sensitivity seems to be associated with those alterations, suggesting a synthetic cytotoxicity relationship. Additionally, these genes are druggable and small molecule inhibition of CREBBP increases DNA damage induction and persistence in response to radiation treatment and increased apoptotic cell death. We hypothesize that the CREBBP/EP300 pathway is both a biomarker and a therapeutically relevant target to sensitize HNSCC to currently used DNA damaging treatments. We propose to examine the genomic basis for this synthetic cytotoxicity and understand how mutations modulate the phenotype. We will also identify global changes to histone acetylation caused by modulation of CREBBP or EP300 and aim to understand how those changes impact the response to DNA damage. Additionally, therapeutic agents that modulate these genes will be tested for their efficacy in preclinical models with the goal of generating sufficient data to justify a clinical trial. Finally, we will perform another in vivo screen to identify other targets that can sensitize to inhibition of CREBBP with reduced toxicity. Overall, this project will examine an exciting new therapeutic target and candidate biomarker for a tumor type that is driven by loss of tumor suppressor genes and has proven difficult to target.

头颈部鳞状细胞癌（HNSCC）是一种来自上肢的多种肿瘤