Extension of Radiotherapy Research

辐射分级、计划、提供和开发辐射组合方面的创新， 化疗改善了晚期中老年癌症的局部区域控制(LRC) 空气消化道(UADT)，包括头颈部鳞状细胞癌(HNSCC)和非小细胞癌 肺癌(NSCLC)，导致更好的生存，但以增加毒性为代价。进行的研究 通过这个项目确定了表皮生长因子受体(EGFR)是一个重要的决定因素 细胞辐射敏感性，阐明了EGFR调控细胞对辐射反应的机制， 并建立了放射与抗EGFR单抗西妥昔单抗的联合应用。 用于局部晚期HNSCC患者的新的、毒性较低的一线治疗。这代表着一个成功的 从替补席到床边的转换只用了九年的时间。然而，关键的结果是 试验表明，LRC还有进一步改善的空间，对远处转移的影响已经 是最低限度的。新出现的数据显示，高水平的胰岛素样生长因子受体1(IGF-1R) 表达与耐药有关，EGFR和IGF-1R之间存在干扰 小路。我们已经产生了初步的临床前证据表明，癌细胞上调IGF-1R 作为对EGFR拮抗剂的反应。这些新的发现使我们提出了以下假设：(1) IGF-1R的结构性或诱导性上调是肿瘤缺乏增强的主要机制 EGFR拮抗剂单独对辐射的反应和(2)共同靶向EGFR和IGF-1R信号转导 途径，使用其各自的单抗西妥昔单抗和A12，结合辐射将 产生比单独阻断EGFR信号转导更好的结果。为了检验这些假设，我们提出了 1)测定A12对体外培养的HNSCCs和NSCLCs的直接放射增敏作用 2)利用人肿瘤移植瘤优化分割放射治疗与A12的结合 模型；3)评估A12在抑制侵袭和转移扩散中的活性 生物发光成像方法；4)评估西妥昔单抗与放射联合治疗的效果。 A12。在令人鼓舞的情况下，结果将作为制定令人信服的临床方案的基础 测试。

Innovations in radiation fractionation, planning, and delivery and development of combinations of radiation, with chemotherapy have improved the local-regional control (LRC) of advanced cancers of the upper aerodigestive track (UADT), including head & neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), resulting in better survival but at the expense of increased toxicity. Studies conducted through this project identified the epidermal growth factor receptor (EGFR) as an important determinant of cellular radiation sensitivity, elucidated mechanisms by which EGFR governs cellular response to radiation, and established the combination of radiation with cetuximab (monoclonal antibody against EGFR) as a novel, less toxic, frontline therapy for patients with locally advanced HNSCC. This represents a successful translation from the bench to bedside in merely a nine year time span. However, the results of the pivotal trial showed that there is room for further improvement in LRC and the impact on distant metastasis has been minimal. Emerging data show that high level of insulin-like growth factor receptor 1 (IGF-1 R) expression is associated with resistance to therapy and that crosstalk exists between EGFR and IGF-1 R pathways. We have generated preliminary preclinical evidence showing that cancer cells upregulate IGF-1 R in response to EGFR antagonists. These new findings led us to propose the following hypotheses: (1) constitutive or induced upregulation of IGF-1 R is a major mechanism for lack of enhancement of tumor response to radiation by EGFR antagonist alone and (2) co-targeting both EGFR and IGF-1 R signaling pathways, using their respective monoclonal antibodies cetuximab and A12, in conjunction with radiation will yield superior outcome than blockade of EGFR signaling alone. To test these hypotheses, we propose the following specific aims: 1) determine the direct radiosensitizing effect of A12 on HNSCCs and NSCLCs in vitro; 2) optimize the combination of fractionated radiotherapy with A12 using human tumor xenograft models; 3) assess the activity of A12 in suppressing invasion and metastatic spread using an bioluminescence imaging method; and 4) assess the effects of combination of radiation with cetuximab and A12. When encouraging, results will serve as the basis for formulating compelling regimen for clinical testing.