Integration of EGFR Inhibitors with Radiochemotherapy in Head and Neck Cancer

EGFR 抑制剂与放化疗结合治疗头颈癌

• 批准号: 8444636
• 负责人: Mukesh K. Nyati
• 金额: $ 28.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444636
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Affect; Aftercare; Age; Aggressive behavior; Biological Markers; Biopsy; Cancer cell line; Cell Cycle; Cetuximab; Cisplatin; Clinical Trials; Data; Deglutition Disorders; Dose; Down-Regulation; EGFR inhibition; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Future; G1 Arrest; Gefitinib; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Health; High Pressure Liquid Chromatography; Histones; Human; Immunoblotting; In Vitro; In complete remission; International; Life; Literature; MAP Kinase Gene; Mass Fragmentography; Measures; Meta-Analysis; Methods; Mitogen-Activated Protein Kinases; Mucositis; Organ Preservation; Outcome; Patient Selection; Patients; Pharmacodynamics; Phase; Phospholipase; Phosphoproteins; Phosphotransferases; Play; Population; Pre-Clinical Model; Preparation; Protein Kinase C; Proteins; Proteomics; Publishing; Radiation; Radiation therapy; Regimen; STAT protein; STAT3 gene; Schedule; Signal Pathway; Signal Transduction; Silicon Dioxide; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Techniques; Testing; Tissue Microarray; Toxic effect; Treatment Protocols; Xenograft procedure; cell killing; chemoradiation; design; epidermal growth factor receptor VIII; experience; extracellular; head and neck cancer patient; improved; in vivo; indexing; novel; novel marker; partial response; pre-clinical; preclinical study; randomized trial; response; standard care; tandem mass spectrometry; treatment response; tumor

DESCRIPTION (provided by applicant): Although chemoradiation for patients with locally advanced head and neck cancer improves survival compared to radiation alone, combination treatment is associated with an increased rate of serious and life threatening mucositis and dysphagia. EGFR plays a key role in head and neck cancer, in that its over-expression is associated with more aggressive behavior, and its blockade increases the survival of patients treated with radiation without increasing (non-skin) toxicity. In addition, we have carried out preclinical studies indicating that a decrease in activation of key signal transduction molecules after cetuximab administration may predict the response to the combination of cetuximab and radiation. The goal of this application is to determine the pharmacodynamic profile of response in patients receiving cetuximab and radiation so that we can determine who benefits from this extremely expensive and moderately toxic therapy. We wish to identify in patients the established preclinical and novel downstream markers of EGFR activity that are associated with EGFR inhibition and eventual response. We also propose preclinical studies to optimize the use of cetuximab in combination with chemotherapy that will be incorporated into future clinical trials. These goals will be achieved through 3 specific aims: Specific Aim 1 is to improve the outcome of patients with locally advanced head and neck squamous cell carcinoma who would not be anticipated to benefit from adding chemotherapy to radiation, and who would typically receive radiation alone, by using cetuximab-radiation. Specific Aim 2 is to discover potential new biomarkers (Aim 2A) and to validate in preclinical models the potential of new and established markers (Aim 2B) of EGFR activity to predict response to cetuximab (with radiation). Specific Aim 3 is to carry out preclinical studies to determine the optimum schedule for combining EGFR inhibition with chemoradiotherapy, with the goal of designing a future clinical trial for patients who are candidates for chemotherapy.

描述（由申请人提供）：尽管与仅放射线相比，局部晚期和颈部癌症患者的化学放疗可以提高生存率，但组合治疗与严重和威胁生命的粘膜炎和吞咽困难的率增加有关。 EGFR在头颈癌中起着关键作用，因为它的过表达与更具侵略性的行为有关，并且其阻滞剂会增加接受辐射治疗的患者的存活，而不会增加（非皮肤）毒性。此外，我们进行了临床前研究，表明在西替昔昔单抗给药后，钥匙信号转导分子的激活减少可能预测对西替辛和辐射的组合的反应。该应用的目的是确定接受西妥昔单抗和放射线的患者的反应的药效学特征，以便我们可以确定谁能从这种非常昂贵和中等毒性的疗法中受益。我们希望在患者中识别与EGFR抑制和最终反应有关的EGFR活性的已建立的临床前和新颖的下游标记。我们还建议临床前研究，以优化西妥昔单抗与化学疗法结合使用，并将其纳入将来的临床试验。这些目标将通过3个特定目标来实现：特定目标1是改善局部先进的头颈鳞状细胞癌的患者的结果，他们不会从将化学疗法添加到放射线中受益，并且通常会单独使用cetuximab-radiation来单独接受放射线。具体目的2是发现潜在的新生物标志物（AIM 2A），并在临床前模型中验证EGFR活性的新标记（AIM 2B）的潜力以预测对西妥昔单抗的反应（带有辐射）。具体目的3是进行临床前研究，以确定将EGFR抑制与化学疗法相结合的最佳时间表，目的是为候选化学疗法的患者设计未来的临床试验。