Intercepting head and neck cancer using functional genomics approaches

项目总结 头颈部鳞状细胞癌(HNSCC)是一种破坏性很强的恶性肿瘤。 发病率、低存活率和有限的治疗选择；大多数病例表现为口腔 肿瘤或口腔鳞癌(OSCC)。细胞命运决定和CSC维护和 扩张是由Wnt/-catenin信号控制的，这是HNSCC病理生物学的基础，然而， HNSCC中Wnt/-catenin失控的细胞、基因组和表观遗传学细节仍未确定。在我们的 最近的研究发现，通过药理学级别的小分子抑制-连环蛋白/cBP信号转导。 抑制剂ICG001和E7386-干扰口腔鳞癌肿瘤生长和转移并升高β-1 口腔鳞状细胞癌原发肿瘤中的连环蛋白/CBP信号转导与肿瘤进展和患者生存不良有关。 在这些初步调查结果的基础上，我们的项目总共包括三个目标。目标1试图定义角色 用小鼠4NQO口服液研究-连环蛋白/CBP在人非小细胞肺癌发生和进展中的作用 致癌模型。在目标2中，我们将验证与-连环蛋白/CBP相关的转录特征。 并将这些数据与公开可用的多组学数据集相结合。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 干预策略和联合治疗的潜在目标。总体而言，我们的项目旨在定义 癌前病变中-连环蛋白/CBP活性与侵袭性细胞的分子联系及鉴定 头颈部癌症的治疗干预。我们推测，抑制β-连环蛋白/CBP活性将 拦截早期疾病并干扰其进展，E7386抑制信号将具有 对口腔鳞癌诊断和治疗的预后价值。

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.