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：
10380839
负责人：
Curtis Pickering
金额：
$ 55.81万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380839
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 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 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 appropriate dose base candidate marker cell type comparative cytotoxic cytotoxicity dosage exhaustion 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.

头颈鳞状细胞癌 (HNSCC) 是一组不同的上颌肿瘤呼吸消化道的治疗效果相对较差，针对性治疗选择也有限。大多数患者是用 DNA 损伤剂（铂、XRT）组合进行处理。最近的基因组特征这些肿瘤尚未确定有针对性的致癌驱动因素，因此强调需要开发合理的基于基因组的方法可提高对诱导 DNA 损伤的治疗的敏感性。我们执行了一个单独或联合对基因组表征的 HNSCC 细胞系进行体内功能基因组筛选 DNA 损伤剂。 CREBBP 或 EP300 的敲低被认为是一种潜在的机制使细胞对 DNA 损伤反应敏感。 CREBBP和EP300是同源多功能含有溴结构域的乙酰转移酶可以调节许多蛋白质和途径。重要的是， CREBBP 和 EP300 在 13% 的 HNSCC 中发生突变，敏感性似乎与这些相关变化，表明合成细胞毒性关系。此外，这些基因是可药物化的并且很小 CREBBP 的分子抑制可增加 DNA 损伤诱导和辐射响应持久性治疗并增加细胞凋亡。我们假设 CREBBP/EP300 途径既是生物标志物和治疗相关靶点，使 HNSCC 对当前使用的 DNA 损伤敏感治疗。我们建议检查这种合成细胞毒性的基因组基础并了解如何突变调节表型。我们还将确定由以下原因引起的组蛋白乙酰化的全局变化 CREBBP 或 EP300 的调节，旨在了解这些变化如何影响对 DNA 的反应损害。此外，将测试调节这些基因的治疗剂的功效临床前模型，旨在生成足够的数据来证明临床试验的合理性。最后我们将表演另一项体内筛选，以确定可以对 CREBBP 抑制敏感并降低毒性的其他靶标。总体而言，该项目将研究一个令人兴奋的新治疗靶点和肿瘤类型的候选生物标志物这是由肿瘤抑制基因的缺失引起的，并且已被证明难以靶向。