Role of Activated EGFR and COX-2 in Metastasis and Escape from Tumor Dormancy

意义 由于局部区域治疗的最新进展，远处转移正在成为头颈部鳞状细胞癌（HNSCC）治疗失败的一种越来越重要的模式。使用T-HEp 3临床前模型，初步数据表明逃离肿瘤休眠和转移表型之间的联系。这些实验，辅以遗传学分析，提示表皮生长因子受体（EGFR）激活和环氧化酶-2（考克斯-2）过表达在HSNC转移中起重要作用。此外，T-HEp 3模型证明尿激酶纤溶酶原激活剂（uPAR）驱动的EGFR的配体非依赖性激活，导致对单克隆抗体（mAB）的内在抗性，该抗体阻止配体与EGFR受体结合。 我们的长期目标是了解如何使用小分子抑制剂选择性地靶向EGFR和考克斯-2来预防转移、维持肿瘤休眠和克服对西妥昔单抗的耐药性。更直接的目标是验证uPAR在抗体-EGFR mAb治疗的固有抗性中的作用。 创新 我们的总体假设提出，EGFR和考克斯-2联合抑制，与有效的局部治疗相结合，可以通过诱导和维持肿瘤休眠有效地预防HNSCC的远处转移。 这代表了HNSCC治疗的全新方法。 具体目标 该假说的具体目标是：1）确定EGFR和考克斯-2在T-HEp 3 HNSCC模型中的休眠逃逸和转移发展中的作用; 2）确定uPAR对抗EGFR mAb的抗性的作用。重新强调该提案的创新：总体而言，这些研究将确定考克斯-2和EGFR在HNSCC远处转移发展中的关键作用，并强调uPAR在抗EGFR mAb内在耐药性中的作用。本课题的研究结果将有助于临床上合理的抗肿瘤转移治疗。 重新强调提案的创新 总之，这些研究将确定考克斯-2和EGFR在HNSCC远处转移发展中的关键作用，并强调uPAR在抗EGFR mAb内在耐药性中的作用。本课题的研究结果将有助于临床上合理的抗肿瘤转移治疗。 关键词：头颈癌，转移，肿瘤休眠，表皮生长因子受体，考克斯-2

Significance Due to recent advances in locoregional treatment, distant metastases are emerging as an increasingly important pattern of treatment failure in head and neck squamous cell carcinoma (HNSCC). Using T-HEp3 preclinical model, preliminary data suggests a link between escape from tumor dormancy and metastatic phenotype. These experiments, supplemented by genetic analyses, suggest an important role for both epidermal growth factor receptor (EGFR) activation and cyclooygeanase-2 (COX-2) overexpression in HSNC metastasis. Further, the T-HEp3 model demonstrates urkinase plasminogen activator (uPAR)-driven ligand-independent activation of EGFR resulting in intrinsic resistance to monoclonal antibodies (mAB) that prevent ligand binding to the EGFR receptor. Our long range goal is to understand how to prevent metastases, maintain tumor dormancy and overcome resistance to cetuximab be selectively targeting EGFR and COX-2 using small molecule inhibitors. A more immediate goal is to validate the role of uPAR in inherent resistance to antibody-EGFR mAb therapy. Innovation Our overarching hypothesis proposes that combined EGFR and COX-2 inhibition, in combination with effective locoregional therapy, can effectively prevent distant metastases in HNSCC by inducing and maintaining tumor dormancy. This represents a completely new approach to HNSCC treatment. Specific Aims The specific aims to this hypothesis will: 1) Determine the role of EGFR & COX-2 in escape from dormancy and metastasis development in T-HEp3 HNSCC model; 2) Determine the role of uPAR on resistance to anti-EGFR mAb. Reemphasis of the proposal's innovation: Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational anti-metastasis therapy in HNSCC. Reemphasis of the proposal's innovation Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational antimetastasis therapy in HNSCC. Keywords: head and neck cancer, metastasis, tumor dormancy, EGFR, COX-2