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

表皮生长因子受体（EGFR）是头颈部肿瘤治疗的重要靶点 鳞状细胞癌（HNSCC）。靶向EGFR的临床策略集中在单克隆抗体上。 抗体（mAb），如西妥昔单抗。西妥昔单抗在体内通过阻断 受体-配体相互作用和Fc γ受体在免疫效应细胞上的接合， 抗体依赖性细胞介导的细胞毒性（ADCC）。我们的初步研究表明肿瘤 TGF-β的细胞自主表达是新生或获得性肿瘤的关键分子决定因素， 癌症对EGFR靶向mAb的耐药性，并为增强抗肿瘤疗效提供了理论基础 通过基于组合或双功能抗体的策略， 肿瘤微环境中的TGF-β。该项目的目的是促进临床 翻译此策略治疗HNSCC;具体目标I：确定肿瘤是否 TGF-β的细胞自主表达抑制HNSCC患者中西妥昔单抗诱导的ADCC。 特定目的II：确定EGFR和EGFR的双重阻断的体内抗肿瘤功效和毒性。 在小鼠中使用HNSCC患者来源的肿瘤异种移植物的TGF-β。具体目标三：确定临床 TGF-β作为HNSCC患者对西妥昔单抗耐药的分子决定因素的相关性，以及 评估一种新型双功能抗EGFR抗体的临床安全性， 肿瘤微环境中的TGF-β。该项目解决了迫切需要有效 针对HNSCC的肿瘤靶向治疗策略：（1）建立肿瘤细胞自主调节的作用， TGF-β表达作为西妥昔单抗耐药患者的关键机制和临床生物标志物 （2）通过新的联合疗法改善HNSCC和其他癌症患者的治疗 基于双功能抗体的策略，同时靶向和抵消EGFR和TGF-β， 肿瘤微环境该项目将利用JHU组织核心的专业知识和资源， 生物统计学核心，并将与项目1和项目4的孢子头颈癌。

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.