Improving epidermal growth factor receptor-targeted of HNSCC by inhibition of tr

表皮生长因子受体(EGFR)是头颈部治疗的重要靶点。 鳞癌(HNSCC)。针对EGFR的临床策略主要集中在单克隆性 抗体(单抗)，如西妥昔单抗。西妥昔单抗体内抗肿瘤作用是通过阻断 受体-配体相互作用和FcGamma受体在免疫效应细胞上的结合 抗体依赖细胞介导的细胞毒性(ADCC)。我们的初步研究表明，肿瘤 转化生长因子-β的细胞自主表达是从头或获得性的关键分子决定因素 肿瘤对EGFR靶向单抗的耐药性，为提高抗肿瘤疗效提供了理论依据 利用基于组合或双功能抗体的策略同时中和抗EGFR单抗 肿瘤微环境中的转化生长因子-β。该项目的目的是为了推进临床 翻译这一治疗HNSCC的策略；具体目标一：确定肿瘤 转化生长因子-β的细胞自主表达抑制西妥昔单抗诱导的HNSCC患者的ADCC。 特异性目的II：测定EGFR和EGFR双重阻断的体内抗肿瘤效果和毒性 使用HNSCC患者来源的小鼠肿瘤移植瘤的转化生长因子-β。具体目标三：确定临床 转化生长因子-β作为HNSCC患者西妥昔单抗耐药的分子决定因素的相关性 一种新型可隔离和封闭的双功能抗EGFR抗体的临床安全性评价 肿瘤微环境中的转化生长因子-β。该项目解决了对有效的 肿瘤靶向治疗HNSCC的策略：(1)确定肿瘤细胞自主的作用 转化生长因子-β作为西妥昔单抗耐药的关键机制和临床标志物的表达 (2)通过新的联合疗法改善HNSCC和其他癌症患者的治疗 基于双功能抗体的同时靶向和拮抗EGFR和TGF-β的策略 肿瘤微环境。该项目将利用JHU组织核心的专业知识和资源， 生物统计核心，并将与孢子头和颈部癌症的项目1和4互动。

The epidermal growth factor receptor (EGFR) is an important target forthe treatment of head and neck squamous cell carcinoma (HNSCC). Clinical strategies to target EGFR have focused on monoclonal antibodies (mAbs), such as cetuximab. Cetuximab executes its antitumor effect in vivo via blockade of receptor-ligand interactions and engagement of Fcgamma receptors on immune effector cells which trigger antibody-dependent cell-mediated cytotoxicity (ADCC). Our preliminary studies demonstrate that tumor cell-autonomous expression of TGF-beta is a key molecular determinant of the de novo or acquired resistance of cancers to EGFR-targeted mAb, and provide a rationale for enhancing the antitumor efficacy of anti-EGFR mAb by combinatorial- or bi-functional antibody-based strategies to simultaneously counteract TGF-beta in the tumor microenvironment. The aims of the project are designed to advance the clinical translation of this strategy for treatment of HNSCC; Specific Aim I: Determine whether tumor cell-autonomous expression of TGF-beta inhibits cetuximab-induced ADCC in patients with HNSCC. Specific Aim II: Determine the in vivo antitumor efficacy and toxicity of dual blockade of EGFR and TGF-beta using HNSCC patient-derived tumor xenografts in mice. Specific Aim III: Determine the clinical relevance of TGF-beta as a molecular determinant of resistance to cetuximab in patients with HNSCC, and evaluate the clinical safety of a novel bi-functional anti-EGFR antibody that can sequester and block TGF-beta in the tumor microenvironment. This project addresses the urgent need for effective tumor-targeted therapeutic strategies against HNSCC by: (1) Establishing the role of tumor cell-autonomous expression of TGF-beta as a key mechanism and clinical biomarker of resistance to cetuximab in patients with HNSCC; (2) Improving the treatment of patients with HNSCC and other cancers via novelcombinatorialor bi-functional antibody-based strategies that simultaneously target and counteract EGFR and TGF-beta in the tumor microenvironment. The project will leverage the expertise and resources of the JHU Tissue Core, Biostatistics Core, and will interact with Projects 1 and 4 of the SPORE-Head and Neck Cancer.