Extension of Radiotherapy Research

放射治疗研究的延伸

• 批准号: 8509643
• 负责人: RAYMOND E MEYN
• 金额: $ 27.51万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509643
• 关键词: Acute; Advanced Malignant Neoplasm; Adverse effects; Blood Vessels; Cancer Model; Cetuximab; Clinical Trials; Clinical Trials Cooperative Group; Data; Development; Distant Metastasis; Dose; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family member; Fractionation; Funding; Funding Mechanisms; Future; Growth Factor Receptors; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Instruction; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Laboratory Finding; Locally Advanced Malignant Neoplasm; Malignant neoplasm of lung; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Outcome; Pathway interactions; Patients; Phase III Clinical Trials; Play; Process; Prognostic Factor; Radiation; Radiation Therapy Oncology Group; Radiation Tolerance; Radiation therapy; Radiotherapy Research; Reaction; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regimen; Relapse; Relative (related person); Research Personnel; Role; Schedule; Signal Pathway; Signal Transduction; Site; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Toxic effect; Translations; Up-Regulation; Work; Xenograft Model; base; bench to bedside; bioluminescence imaging; cancer cell; chemotherapy; experience; imaging modality; improved; in vivo; innovation; novel; overexpression; pre-clinical; research clinical testing; response; sound; therapy resistant; tumor; tumor growth; tumor xenograft

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.

辐射分离、规划以及辐射组合的交付和开发方面的创新， 联合化疗改善了上消化道晚期癌症的局部区域控制（LRC） 呼吸消化道 (UADT)，包括头颈鳞状细胞癌 (HNSCC) 和非小细胞癌 肺癌（NSCLC），可提高生存率，但代价是毒性增加。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 控制细胞对辐射反应的机制， 并建立了放射治疗与西妥昔单抗（针对 EGFR 的单克隆抗体）的联合治疗 针对局部晚期 HNSCC 患者的新型、毒性较小的一线疗法。这代表着一次成功 从实验室到临床的转变仅仅用了九年的时间。然而，关键的结果 试验表明LRC还有进一步改善的空间，对远处转移的影响已 是最小的。新数据显示高水平的胰岛素样生长因子受体 1 (IGF-1 R) 表达与治疗耐药相关，并且 EGFR 和 IGF-1 R 之间存在串扰 途径。我们已经生成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的组成型或诱导性上调是肿瘤缺乏增强的主要机制 单独使用 EGFR 拮抗剂对辐射的反应以及 (2) 共同靶向 EGFR 和 IGF-1 R 信号传导 途径，使用各自的单克隆抗体西妥昔单抗和 A12，结合辐射将 比单独阻断 EGFR 信号传导产生更好的结果。为了检验这些假设，我们提出 以下具体目标：1) 确定 A12 对 HNSCC 和 NSCLC 的直接放射增敏作用 体外； 2）利用人肿瘤异种移植物优化分次放疗与A12的组合 模型； 3) 使用 A12 评估 A12 在抑制侵袭和转移扩散方面的活性 生物发光成像方法； 4) 评估放射治疗与西妥昔单抗联合治疗的效果 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 测试。