EGFRvIII expression, signaling and treatment in SCC of the head and neck

头颈部鳞状细胞癌中 EGFRvIII 的表达、信号传导和治疗

• 批准号: 8000381
• 负责人: Sarah E. Wheeler
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000381
• 关键词: Alternative Splicing; Cells; Cetuximab; Clinical; Development; Disease; Epidermal Growth Factor Receptor; Erbitux; Exons; FDA approved; Glioma; Head and Neck Squamous Cell Carcinoma; Head and neck structure; In Vitro; Lead; Malignant Neoplasms; Mediating; Messenger RNA; Monoclonal Antibodies; Morbidity - disease rate; Oncogenic; Pathway interactions; Patients; Phenotype; RNA Splicing; Receptor Protein-Tyrosine Kinases; Regulatory Element; Reporting; Resistance; STAT3 gene; Signal Pathway; Signal Transduction; Site; System; Therapeutic; Transcript; Treatment Protocols; United States; Variant; Work; design; effective therapy; epidermal growth factor receptor VIII; genetic regulatory protein; in vivo; mortality; mouth squamous cell carcinoma; overexpression; protein expression; public health relevance; receptor expression; resistance mechanism; response; src-Family Kinases; therapeutic target; tumor

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma of the head and neck (OSCC) is the sixth most common cancer in the United States. Development of more targeted therapies is needed to reduce the high mortality rate seen with this cancer. Epidermal Growth Factor Receptor (EGFR) has emerged as a plausible therapeutic target for OSCC. Overexpression of this tyrosine kinase receptor has been characterized in OSCC and found to be present in up to ~90% of tumors where expression levels correlate with decreased patient survival. In 2006 cetuximab (Erbitux; Imclone Systems) (an EGFR specific monoclonal antibody) became the first new FDA-approved treatment for SCCHN in 45 years. Despite ubiquitous EGFR expression in OSCC, cetuximab has demonstrated limited clinical responses as a single agent (~10%). One potential mechanism of resistance to the wild type EGFR blockade is the expression of the constitutively active EGF receptor variant 3 (EGFRvIII). Sok et al. (2006) reported the presence of EGFRvIII in approximately 40% of SCCHN, and demonstrated in vitro and in vivo resistance of EGFRvIII expressing cells to cetuximab. In glioma (where EGFRvIII has been best characterized) STAT3 and Src family kinases (SFKs) have been elucidated as key regulatory proteins in the oncogenic phenotype of EGFRvIII. The mechanism of EGFRvIII protein expression is still unexplored in OSCC. Additionally, differential signaling pathways mediated through EGFRvIII remain relatively uncharacterized in SCCHN. I hypothesize that the mechanism contributing to EGFRvIII expression in OSCC is alteration of the mRNA splice sites for exons 2-7 causing alternate splicing of the EGFR transcript. Further, I hypothesize that EGFRvIII specific signaling through STAT3 and SFKs contributes to the oncogenic phenotype of EGFRvIII and that blocking these regulatory elements will lead to enhanced response to EGFR targeting agents. PUBLIC HEALTH RELEVANCE: OSCC is a devastating disease with high mortality and morbidity. Current treatments for OSCC are still limited with many patients demonstrating resistance to treatment. The work proposed here will elucidate a more thorough understanding of the pathways of therapeutic resistance and facilitate the design of more effective treatment regimens.

描述（由申请人提供）：头颈部口腔鳞状细胞癌（OSCC）是美国第六大常见癌症。需要开发更有针对性的治疗方法来降低这种癌症的高死亡率。表皮生长因子受体（EGFR）已成为一个合理的治疗目标，口腔鳞状细胞癌。这种酪氨酸激酶受体的过表达在口腔鳞状细胞癌中有特征性表现，并且发现在高达90%的肿瘤中存在，其中表达水平与患者生存率降低相关。2006年，西妥昔单抗（Erbitux; Imclone Systems）（一种EGFR特异性单克隆抗体）成为45年来FDA批准的首个新的SCCHN治疗药物。尽管EGFR在口腔鳞状细胞癌中普遍表达，但西妥昔单抗作为单一药物的临床反应有限（约10%）。对野生型EGFR阻断的一种潜在的抗性机制是组成型活性EGF受体变体3（EGFRvIII）的表达。Sok et al.（2006）报告了约40%的SCCHN中存在EGFRvIII，并证明了表达EGFRvIII的细胞对西妥昔单抗的体外和体内耐药性。在神经胶质瘤中（其中EGFRvIII已被最好地表征），STAT 3和Src家族激酶（SFK）已被阐明为EGFRvIII致癌表型中的关键调节蛋白。EGFRvIII蛋白在口腔鳞癌中的表达机制尚不清楚。此外，通过EGFRvIII介导的差异信号传导途径在SCCHN中仍然相对未表征。我推测，在口腔鳞癌中促进EGFRvIII表达的机制是外显子2-7的mRNA剪接位点的改变，导致EGFR转录物的选择性剪接。此外，我假设通过STAT 3和SFKs的EGFRvIII特异性信号传导有助于EGFRvIII的致癌表型，阻断这些调控元件将导致对EGFR靶向药物的反应增强。 公共卫生相关性：口腔鳞状细胞癌是一种具有高死亡率和发病率的毁灭性疾病。目前对口腔鳞状细胞癌的治疗仍然有限，许多患者表现出对治疗的抵抗。本文提出的工作将阐明对治疗耐药途径的更透彻的理解，并有助于设计更有效的治疗方案。