Molecular signatures of HNSCC in response to targeted therapies

描述(由申请人提供)：组织病理学相似的肿瘤通常代表不同的疾病过程，由不同的致癌事件和途径驱动。认识到肿瘤之间驱动路径的这种差异显然是提高针对这些路径的治疗成功率的关键。表皮生长因子受体(EGFR)在头颈部鳞状细胞癌(HNSCC)患者中的表达具有预后意义，针对该受体的抗体已在临床上被证明在HNSCC患者中具有活性。EGFR在95%以上的HNSCC中高表达，最近在42%的HNSCC中发现了截断突变EGFR Variant III(EGFRv11)。EGFRv11总是与野生型受体共表达，可能反映了单个细胞或肿瘤内细胞克隆的异质性。这种异质性可能是临床上抵抗靶向癌症治疗的重要机制。由于EGFRv11是独立于配体结合而被结构性激活的，因此推测它是西妥昔单抗耐药的一种机制，通过阻断配体结合来抑制EGFR的激活。基于这些数据，我们假设：1)EGFRv11是致癌的，并与HNSCC的西妥昔单抗耐药有关；2)激活的EGFR基因表达信号的存在将使我们能够选择对EGFR抑制剂有更高反应可能性的HNSCC患者。我们的第一个目标是在一个基因定义良好的HaCaT细胞过度表达EGFR的模型系统中确定激活的EGFR信号，并表征EGFRv11在HaCaT细胞中的致癌特性。我们还将在这个模型系统中检测EGFR配体依赖或配体非依赖激活所调节的基因表达差异。第二个目标是确定HNSCC细胞系中被激活的EGFR信号，以测试和提炼该信号作为临床对EGFR抑制剂的反应的生物标志物。我们还将确定与EGFR通路的激活和抑制共同调节的新基因/通路，以确定西妥昔单抗的非靶点效应、耐药机制，并为与现有的EGFR抑制剂联合治疗提供理论依据。我们的第三个目标是确定从HaCaT细胞和HNSCC细胞系产生的激活的EGFR信号以及EGFRv11突变作为西妥昔单抗治疗HNSCC患者临床反应的生物标志物的存在。最终，我们预计这项研究的结果将转化为HNSCC患者改善患者选择和优化EGFR抑制剂的治疗益处。

DESCRIPTION (provided by applicant): Histopathologically similar neoplasms often represent diverse disease processes driven by distinct oncogenic events and pathways. Recognition of such differences in driving pathways between tumors is clearly the key to improving the success rate of therapies targeting these pathways. Epidermal growth factor receptor (EGFR) expression has prognostic significance in patients with head and neck squamous cell carcinoma (HNSCC) and antibodies targeting this receptor have been demonstrated in the clinic to be active in a subset of HNSCC patients. EGFR is overexpressed in over 95% of HNSCC and recently a truncation mutation, EGFR variant III (EGFRvlll), was found in 42% of HNSCC. EGFRvlll is always found with the wild-type receptor in co-expression, perhaps reflecting heterogeneity in individual cells or within clones of cells within a tumor. This heterogeneity may underlie clinically important mechanisms of resistance to targeted cancer treatment. Because EGFRvlll is constitutively activated independent of ligand-binding, it is postulated to be a mechanism of resistance to cetuximab, which inhibits EGFR activation by blocking ligand binding. Based on these data, we hypothesize that; 1) EGFRvlll is oncogenic and associated with cetuximab resistance in HNSCC, 2) the presence of an activated EGFR gene expression signature will allow us to select HNSCC patients with an increased likelihood of response to EGFR inhibitors. Our first Aim is to determine the activated EGFR signature in a genetically well defined model system of HaCaT cells overexpressing EGFR and to characterize the oncogenic properties of EGFRvlll in HaCaT cells. We will also examine gene expression differences regulated by ligand-dependent or ligand-independent activation of EGFR in this model system. The second Aim is to determine the activated EGFR signature in HNSCC cell lines to test and refine the signature as a biomarker of clinical response to EGFR inhibitors. We will also determine novel genes/pathways that are co-regulated with activation and inhibition of EGFR pathways to identify the off-target effect of cetuximab, mechanism of resistance and generate a rationale for combination therapy with current EGFR inhibitors. Our third aim is to determine presence of the activated EGFR signature generated from HaCaT cells and HNSCC cell lines and the EGFRvlll mutation as biomarkers of clinical response in HNSCC patients treated with cetuximab monotherapy. Ultimately, we expect that the findings from this study will be translated into improved patient selection and optimized treatment benefits from EGFR inhibitors in HNSCC patients.