Extension of Radiotherapy Research

辐射分割、规划和输送方面的创新，以及辐射组合的开发， 化疗改善了晚期癌症的局部区域控制（LRC） 呼吸消化道癌（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 通过该项目确定了表皮生长因子受体（EGFR）作为一个重要的决定因素， 细胞辐射敏感性，阐明了EGFR控制细胞对辐射反应的机制， 并建立了辐射与西妥昔单抗（抗EGFR的单克隆抗体）的组合， 局部晚期HNSCC患者的新型、毒性较小的一线治疗。这是一个成功的 在短短九年的时间里从法官变成了医生。然而，关键的结果 一项试验表明，LRC还有进一步改善的空间，对远处转移的影响 是最小的。新的数据表明，高水平的胰岛素样生长因子受体1（IGF-1 R） EGFR和IGF-1 R的表达与对治疗的抵抗有关， 途径。我们已经产生了初步的临床前证据，表明癌细胞上调IGF-1 R 对EGFR拮抗剂的反应。这些新发现使我们提出以下假设：（1） IGF-1 R的组成性或诱导性上调是缺乏肿瘤增强的主要机制 通过单独的EGFR拮抗剂对辐射的反应和（2）共靶向EGFR和IGF-1 R信号传导 使用它们各自的单克隆抗体西妥昔单抗和A12，结合放射治疗， 产生比单独阻断EGFR信号传导更好的上级结果。为了验证这些假设，我们提出了 1）确定A12对HNSCC和NSCLC的直接放射增敏作用， 体外实验; 2）优化A12与分次放疗的联合应用 模型; 3）评估A12在抑制侵袭和转移性扩散中的活性， 生物发光成像方法;和4）评估放射与西妥昔单抗和 A12。当令人鼓舞时，结果将作为制定令人信服的临床治疗方案的基础。 试验.

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.