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

• 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
• 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

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）是一组不同的肿瘤， 呼吸消化道，结果相对较差，靶向治疗选择有限。大多数患者 用DNA损伤剂（铂，XRT）的组合治疗。最近的基因组特征 这些肿瘤尚未确定可靶向的致癌驱动因素，因此强调需要开发合理的 基于基因组的方法，以增加对诱导DNA损伤的治疗的敏感性。我们进行了一次 在单独或与以下组合的基因组表征的HNSCC细胞系中进行体内功能性基因组筛选 DNA破坏剂。CREBBP或EP 300的敲低被鉴定为一种潜在的机制， 使细胞对DNA损伤反应敏感。CREBBP和EP 300是同源多功能的 溴结构域乙酰转移酶，可以调节许多蛋白质和途径。重要的是， CREBBP和EP 300在13%的HNSCC中突变，敏感性似乎与这些突变相关。 改变，表明合成的细胞毒性关系。此外，这些基因是药物和小 CREBBP的分子抑制增加了DNA损伤诱导和对辐射响应的持续性 治疗和增加的凋亡性细胞死亡。我们假设CREBBP/EP 300通路是一个神经系统， 使HNSCC对目前使用的DNA损伤敏感的生物标志物和治疗相关靶标 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因素引起的组蛋白乙酰化的全局变化： CREBBP或EP 300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在以下方面的功效： 临床前模型，目的是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 另一种体内筛选以鉴定可对CREBBP的抑制敏感且毒性降低的其它靶标。 总的来说，这个项目将研究一个令人兴奋的新的治疗目标和候选生物标志物的肿瘤类型 这是由肿瘤抑制基因的丢失驱动的，并且已被证明难以靶向。