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: 8100179
• 负责人: Sarah E. Wheeler
• 金额: $ 4.08万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100179
• 关键词: Alternative Splicing; Anchorage-Independent Growth; Apoptosis; Biochemical Markers; Biological Models; Cell Line; Cells; Cetuximab; Chicago; Clinical; DNA; Databases; Development; Disease; Dominant-Negative Mutation; EGFR Protein Overexpression; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erbitux; Exons; FDA approved; Freezing; Gene Amplification; Genomics; Glioma; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immunotoxins; In Vitro; Incidence; Introns; Laboratories; Lead; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular Target; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; NOD/SCID mouse; Normal tissue morphology; Oncogenic; Pathway interactions; Patients; Personal Communication; Phenotype; Proteins; RNA Splicing; Receptor Protein-Tyrosine Kinases; Regulatory Element; Reporting; Research Personnel; Resistance; Role; Saline; Sampling; Screening procedure; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Specimen; Stat3 protein; System; Therapeutic; Therapeutic Effect; Transcript; Treatment Protocols; United States; Universities; Variant; Western Blotting; Work; Xenograft Model; design; effective therapy; epidermal growth factor receptor VIII; genetic regulatory protein; human disease; in vivo; in vivo Model; inhibitor/antagonist; mRNA Precursor; mortality; mouth squamous cell carcinoma; overexpression; protein expression; receptor expression; resistance mechanism; response; src-Family Kinases; therapeutic target; tumor; tumor growth; vector; vector control

PROJECT SUMMARY 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.

项目概要 口腔头颈鳞状细胞癌 (OSCC) 是美国第六大常见癌症。需要开发更有针对性的疗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 OSCC 的合理治疗靶点。这种酪氨酸激酶受体的过度表达已在 OSCC 中得到表征，并发现其存在于高达约 90% 的肿瘤中，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 批准的第一个新的 SCCHN 治疗方法。尽管 EGFR 在 OSCC 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%）。抵抗野生型 EGFR 阻断的一种潜在机制是组成型活性 EGF 受体变体 3 (EGFRvIII) 的表达。索克等人。 (2006)报道了大约 40% 的 SCCHN 中存在 EGFRvIII，并证明了 EGFRvIII 表达细胞对西妥昔单抗的体外和体内耐药性。在神经胶质瘤（其中 EGFRvIII 得到了最好的表征）中，STAT3 和 Src 家族激酶 (SFK) 已被阐明为 EGFRvIII 致癌表型的关键调节蛋白。 EGFRvIII 蛋白在 OSCC 中表达的机制尚未被探索。此外，通过 EGFRvIII 介导的差异信号通路在 SCCHN 中仍然相对不具有特征。我推测 OSCC 中 EGFRvIII 表达的机制是外显子 2-7 mRNA 剪接位点的改变导致 EGFR 转录物的交替剪接。此外，我推测通过 STAT3 和 SFK 的 EGFRvIII 特异性信号传导有助于 EGFRvIII 的致癌表型，并且阻断这些调节元件将导致对 EGFR 靶向药物的反应增强。