Combining BET protein inhibitors with radiation in HPV oropharyngeal cancer

BET 蛋白抑制剂与放射治疗 HPV 口咽癌的联合治疗

基本信息

批准号：
10578185
负责人：
Gopal Iyer
金额：
$ 21.19万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-08 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578185
关键词：
Address Apoptosis Blood Bromodomain Bromodomains and extra-terminal domain inhibitor Cancer Etiology Cell Cycle Cell Line Cells Cessation of life Characteristics Chemicals Cisplatin Clinical Trials Complete Blood Count Country DNA DNA Crosslinking DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Gene Data Deglutition Disorders Dependence Diagnosis Dose Double Strand Break Repair Drug Targeting Enteral Feeding Family Gene Expression Generations Genes Genetic Transcription Genomic Instability Genomics Goals Growth HPV oropharyngeal cancer Human Papillomavirus Immunohistochemistry In Vitro Incidence Individual Kinetics Lead Length Low Dose Radiation Malignant Epithelial Cell Malignant neoplasm of cervix uteri Measurement Measures Modification Molecular Oropharyngeal Oropharyngeal Neoplasms Oropharyngeal Squamous Cell Carcinoma Output Pathway interactions Patient Selection Patients Pattern Population Proliferating Proteins Quality of life RNA Radiation Radiation Dose Unit Radiation therapy Research Series Specificity Subgroup Surrogate Markers Survival Analysis Survival Rate Testing Therapeutic Tissues Toxic effect Transcriptional Regulation Treatment Protocols Treatment-related toxicity Tumor Cell Line Tumor Volume USP6 gene United States Viral Viral Genes Viral Genome Viral Markers Virus Integration Woman biomarker selection cancer cell comorbidity design efficacy testing established cell line experimental study gene repression human papilloma virus oropharyngeal squamous cell carcinoma improved in vivo inhibitor knock-down malignant oropharynx neoplasm member men mouse model neoplastic cell new therapeutic target patient derived xenograft model pleiotropism preservation programs recruit response secondary endpoint standard of care targeted treatment transcriptome sequencing treatment strategy tumor tumor eradication tumor growth tumor progression tumor xenograft viral DNA

Address Apoptosis Blood Bromodomain Bromodomains and extra-terminal domain inhibitor Cancer Etiology Cell Cycle Cell Line Cells Cessation of life Characteristics Chemicals Cisplatin Clinical Trials Complete Blood Count Country DNA DNA Crosslinking DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Gene Data Deglutition Disorders Dependence Diagnosis Dose Double Strand Break Repair Drug Targeting Enteral Feeding Family Gene Expression Generations Genes Genetic Transcription Genomic Instability Genomics Goals Growth HPV oropharyngeal cancer Human Papillomavirus Immunohistochemistry In Vitro Incidence Individual Kinetics Lead Length Low Dose Radiation Malignant Epithelial Cell Malignant neoplasm of cervix uteri Measurement Measures Modification Molecular Oropharyngeal Oropharyngeal Neoplasms Oropharyngeal Squamous Cell Carcinoma Output Pathway interactions Patient Selection Patients Pattern Population Proliferating Proteins Quality of life RNA Radiation Radiation Dose Unit Radiation therapy Research Series Specificity Subgroup Surrogate Markers Survival Analysis Survival Rate Testing Therapeutic Tissues Toxic effect Transcriptional Regulation Treatment Protocols Treatment-related toxicity Tumor Cell Line Tumor Volume USP6 gene United States Viral Viral Genes Viral Genome Viral Markers Virus Integration Woman biomarker selection cancer cell comorbidity design efficacy testing established cell line experimental study gene repression human papilloma virus oropharyngeal squamous cell carcinoma improved in vivo inhibitor knock-down malignant oropharynx neoplasm member men mouse model neoplastic cell new therapeutic target patient derived xenograft model pleiotropism preservation programs recruit response secondary endpoint standard of care targeted treatment transcriptome sequencing treatment strategy tumor tumor eradication tumor growth tumor progression tumor xenograft viral DNA

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项目摘要

PROJECT SUMMARY/ABSTRACT: During the past decade, oropharyngeal cancer surpassed cervical cancer, becoming the most common cancer caused by human papillomavirus (HPV). Nearly 20,000 oropharyngeal cancer cases are diagnosed among men and women in the United States annually. Despite favorable long-term survival, current non-targeted cisplatin/radiation treatment protocols lead to significant treatment toxicities. De-escalating radiation doses with alternative targeted therapies would be critical for limiting treatment-related toxicities and improving patient quality of life. To address this, we propose to reduce the transcriptional output of viral genes and DNA damage response (DDR) by reducing its dependence on a transcriptional co-regulator bromodomain protein, BRD4, expressed in the oropharyngeal tissue. We propose that DDR deficiencies can be induced by second-generation bromodomain-specific chemical inhibitors in HPV oropharyngeal tumors. This chemically induced DDR deficient state delays the kinetics of DNA repair, thereby causing genomic instability. With tumors in this fragile state, administering optimal radiation doses will result in genomic catastrophe leading to eradicating tumors. We established that a first-generation inhibitor that targets both bromodomains BD1 and BD2 of BRD4 preferentially reduced viral and DDR gene expression of a subset of HPV tumors, which harbored disrupted viral genomes over non-disrupted viral genomes. However, pan-BD domain inhibition could give rise to pleiotropic effects. We used second-generation domain-specific inhibitors introduced in 2020 on HPV tumor cell lines to refine the pan- BD inhibition approach. We observed preferential domain-specific transcriptional regulation. While BD2 domain inhibition downregulated DDR response in disrupted viral tumors, BD1 upregulated anti-viral gene expression in non-disrupted viral tumors. These results guide us to postulate that patients selected upfront for disrupted viral genomes can be matched for BD domain-specific inhibitor and de-escalated radiation treatments. We will use in vitro and in vivo approaches to address a) efficacy of BD domain-specific inhibitors towards creating a DDR- deficient state by measuring viral gene expression and quantifying DDR response kinetics, and test its on-target efficacy in BRD4 knockdown and BD1 and BD2 domain-specific deleted tumor cells, b) Optimize the dose of radiation sufficiently to preserve the efficacy of BD domain-specific inhibition in patient-derived xenograft mice models with secondary endpoint analyses of survival, tumor volume growth, apoptosis, complete blood count panel for toxicity and immunohistochemistry for proliferation and DNA repair proteins.

项目摘要/摘要：在过去的十年中，口咽癌超越了宫颈癌，成为最常见的癌症由人乳头瘤病毒（HPV）引起。男性诊断出近20,000例口咽癌病例和每年在美国的妇女。尽管长期生存良好，但目前不针对顺铂/辐射治疗方案导致重大治疗毒性。降低辐射剂量替代靶向疗法对于限制与治疗相关的毒性和改善患者至关重要生活质量。为了解决这个问题，我们建议减少病毒基因和DNA损伤的转录输出响应（DDR）通过减少其对转录共同调节剂brd4，brd4的依赖性在口咽组织中表达。我们建议可以通过第二代诱导DDR缺陷 HPV口咽肿瘤中的溴结构域特异性化学抑制剂。这种化学诱导的DDR缺乏状态延迟了DNA修复的动力学，从而导致基因组不稳定性。肿瘤处于这种脆弱状态，服用最佳辐射剂量将导致基因组灾难导致根除肿瘤。我们确定靶向BRD4的溴a和Bd2的第一代抑制剂优先 HPV肿瘤子集的病毒和DDR基因表达降低，该子集对病毒基因组的含有干扰超过非干扰病毒基因组。但是，PAN-BD结构域的抑制可能会引起多效效应。我们在2020年在HPV肿瘤细胞系上引入的使用第二代特异性抑制剂，以完善泛池 BD抑制方法。我们观察到优先域特异性的转录调控。而BD2域抑制作用下调病毒肿瘤中的DDR反应，BD1上调抗病毒基因表达非干扰病毒肿瘤。这些结果指导我们假设患者预先选择了病毒破坏的病毒可以将基因组与BD结构域特异性抑制剂和降级辐射处理相匹配。我们将使用 a）BD域特异性抑制剂在创建DDR-的疗效中的体外和体内方法通过测量病毒基因表达和量化DDR反应动力学并测试其靶标的不足状态 BRD4敲低和BD1和BD2域特异性缺失肿瘤细胞的功效，b）优化剂量充分的辐射以保持BD结构域特异性抑制在患者衍生异种移植小鼠中的功效具有生存期，肿瘤体积生长，凋亡，完全血数的次要端点分析的模型毒性和免疫组织化学面板增殖和DNA修复蛋白。