Intercepting head and neck cancer using functional genomics approaches

使用功能基因组学方法拦截头颈癌

基本信息

批准号：
10285987
负责人：
Anthony Federico
金额：
$ 4.04万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285987
关键词：
Automobile Driving Bayesian Analysis Benign Binding Binding Proteins CREBBP gene Cancerous Carcinogens Carcinoma Carcinoma in Situ Cell Maintenance Cell-Cell Adhesion Cells Cetuximab Combined Modality Therapy Cyclic AMP DNA Sequence Alteration Data Data Set Development Diagnosis Disease E-Cadherin Elements Epidermal Growth Factor Receptor Epigenetic Process Epithelial FDA approved Gene Expression Gene Expression Profile Genomic approach Genomics Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Heterogeneity Human Immunocompetent Immunotherapy Intercept Intervention Knowledge Lesion Link Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Abnormality Monoclonal Antibodies Morbidity - disease rate Morphology Mouth Carcinoma Mouth Neoplasms Mus Neoplasm Metastasis Nuclear Oncogenic Oral Pathway Analysis Pathway interactions Patients Pharmacology Phenotype Process Regulator Genes Resistance Role Sample Size Signal Pathway Signal Transduction Signaling Protein Survival Rate Therapeutic Intervention Venus Zebrafish advanced disease anti-PD-1 beta catenin cancer stem cell clinical phenotype combinatorial draining lymph node druggable target functional genomics genetic signature high dimensionality histone acetyltransferase human tissue in silico in vivo Model inhibitor/antagonist malignant mouth neoplasm mouse model mouth squamous cell carcinoma multiple omics network models novel oral carcinogenesis oral lesion predictive modeling premalignant prognostic value programs reconstruction response small molecule inhibitor targeted treatment tool transcriptome sequencing tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is a devastating malignancy associated with high morbidity, poor survival rates, and limited treatment options; the majority of cases presenting as oral cavity tumors, or oral squamous cell carcinoma (OSCC). Cell fate determination and CSC maintenance and expansion are controlled by Wnt/-catenin signaling, shown to underlie HNSCC pathobiology however, the cellular, genomic and epigenetic details of Wnt/-catenin deregulation in HNSCC remain undefined. In our recent studies, we found inhibition of -catenin/CBP signaling – via pharmacological grade small molecule inhibitors, ICG-001 and E7386 – interferes with OSCC tumor growth and metastasis and elevated β- catenin/CBP signaling in primary OSCC tumors is associated with tumor progression and poor patient survival. Building on these preliminary findings, our project includes a total of three aims. Aim 1 seeks to define the role of -catenin/CBP in HNSCC initiation and progression to advanced disease using the murine 4NQO oral carcinogenesis model. In Aim 2 we will validate transcriptional signatures associated with -catenin/CBP in pre-cancerous human tissues and integrate this data with publicly available multi-omics datasets. Lastly, Aim 3 plans to reconstruct gene regulatory networks using high-dimensional Bayesian inference to use in modeling potential targets for intervention strategies and combinatorial therapies. Overall, our project aims to define molecular links between -catenin/CBP activity and aggressive cells in pre-cancerous lesions, and to identify therapeutic interventions in head and neck cancer. We postulate that inhibition of β-catenin/CBP activity will intercept early disease and interfere with its progression, and that the E7386 inhibition signature will have prognostic value for OSCC diagnosis and treatment.

项目概要头颈鳞状细胞癌 (HNSCC) 是一种与高死亡率相关的毁灭性恶性肿瘤。发病率高，生存率低，治疗选择有限；大多数病例表现为口腔问题；肿瘤或口腔鳞状细胞癌 (OSCC) 细胞命运测定和 CSC 维持和扩增由 Wnt/-catenin 信号传导控制，该信号传导是 HNSCC 病理学的基础，然而， HNSCC 中 Wnt/-catenin 失调的细胞、基因组和表观遗传学细节仍不清楚。最近的研究，我们发现通过药理学级小分子抑制 -连环蛋白/CBP 信号传导抑制剂 ICG-001 和 E7386 – 干扰 OSCC 肿瘤生长和转移并升高 β- 原发性 OSCC 肿瘤中的连环蛋白/CBP 信号传导与肿瘤进展和患者生存率低相关。基于这些初步发现，我们的项目总共包括三个目标，旨在定义该角色。使用小鼠 4NQO 口服液研究 -catenin/CBP 在 HNSCC 发生和进展为晚期疾病中的作用在目标 2 中，我们将验证与 β-catenin/CBP 相关的转录特征。最后，目标 3。计划使用高维贝叶斯推理重建基因调控网络以用于建模总体而言，我们的项目旨在确定干预策略和组合疗法的潜在目标。 -catenin/CBP 活性与癌前病变中侵袭性细胞之间的分子联系，并确定我们假设抑制 β-连环蛋白/CBP 活性将有助于治疗头颈癌。拦截早期疾病并干扰其进展，并且 E7386 抑制特征将具有对 OSCC 诊断和治疗的预后价值。