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.

项目摘要 头部和颈部口服鳞状细胞癌（OSCC）是美国第六大最常见的癌症。需要开发更多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的合理治疗靶标。该酪氨酸激酶受体的过表达已在OSCC中进行表征，并发现在大约90％的肿瘤中存在，其中表达水平与患者的生存率降低相关。 2006年，西妥昔单抗（Erbitux; imclone Systems）（EGFR特异性单克隆抗体）成为45年内SCCHN的首次新型FDA批准的治疗方法。尽管OSCC中无处不在的EGFR表达，但西妥昔单抗作为单个药物的临床反应有限（〜10％）。对野生型EGFR阻滞的抗性的一种潜在机制是组成性活跃的EGF受体变体3（EGFRVIII）的表达。 Sok等。 （2006年）报道了大约40％的SCCHN中存在EGFRVIII，并在体外表现出EGFRVIII表达细胞对Cetuximab的体外耐药性。在神经胶质瘤中（EGFRVIII的表征最佳）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蛋白表达的机制在OSCC中仍未探索。另外，通过EGFRVIII介导的差分信号通路在SCCHN中仍然相对未表征。我假设在OSCC中促成EGFRVIII表达的机制是外显子2-7的mRNA剪接位点的改变，导致EGFR转录物的替代剪接。此外，我假设通过STAT3和SFK的EGFRVIII特定信号传导有助于EGFRVIII的致癌表型，并且阻止这些调节元素将导致对EGFR靶向药物的反应增强。