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

描述（申请人提供）：口腔头颈部鳞状细胞癌（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）已成为一种可行的OSCC治疗靶点。这种酪氨酸激酶受体的过表达已在OSCC中被表征，并发现存在于高达90%的肿瘤中，其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批准的首个治疗SCCHN的新药物。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阻断的一个潜在机制是组成型活性EGF受体变体3 （EGFRvIII）的表达。Sok等人（2006）报道了大约40%的SCCHN中存在EGFRvIII，并在体外和体内证明了表达EGFRvIII的细胞对西妥昔单抗的耐药性。在胶质瘤中，STAT3和Src家族激酶（SFKs）已被阐明为EGFRvIII致癌表型的关键调节蛋白。EGFRvIII蛋白在OSCC中的表达机制尚不清楚。此外，通过EGFRvIII介导的差异信号通路在SCCHN中仍然相对不明确。我假设在OSCC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转录物的交替剪接。此外，我假设通过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。

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.