Intercepting head and neck cancer using functional genomics approaches

使用功能基因组学方法拦截头颈癌

• 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
• 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

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.

项目摘要 头颈部鳞状细胞癌（HNSCC）是一种毁灭性的恶性肿瘤， 发病率，生存率低，治疗选择有限;大多数病例表现为口腔 肿瘤或口腔鳞状细胞癌（OSCC）。细胞命运确定和CSC维持以及 扩张是由Wnt/β-连环蛋白信号传导控制的，显示为HNSCC病理学的基础，然而， HNSCC中Wnt/β-连环蛋白失调的细胞、基因组和表观遗传学细节仍不清楚。在我们 最近的研究，我们发现抑制β-catenin/CBP信号-通过药理级小分子 抑制剂ICG-001和E7386 -干扰OSCC肿瘤生长和转移， 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。 在这些初步研究结果的基础上，我们的项目包括三个目标。目标1旨在确定 使用小鼠4 NQO口服给药的HNSCC启动和进展为晚期疾病中β-连环蛋白/CBP的表达 致癌模型在目标2中，我们将验证与β-连环蛋白/CBP相关的转录特征， 癌前人类组织，并将这些数据与公开可用的多组学数据集整合。最后，目标3 计划使用高维贝叶斯推理重建基因调控网络，用于建模 干预策略和组合疗法的潜在目标。总的来说，我们的项目旨在定义 β-连环蛋白/CBP活性与癌前病变中的侵袭性细胞之间的分子联系， 头颈癌的治疗干预。我们推测，抑制β-catenin/CBP活性， 阻断早期疾病并干扰其进展，并且E7386抑制特征将具有 OSCC诊断和治疗的预后价值。