Integration of EGFR Inhibitors with Radiochemotherapy

EGFR 抑制剂与放化疗的整合

基本信息

批准号：
7448853
负责人：
THEODORE S LAWRENCE
金额：
$ 13.74万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448853
关键词：
Affect Aftercare Aggressive behavior Biological Markers Biological Preservation Biopsy Cancer cell line Cell Cycle Cells Cetuximab Cisplatin Cisplatin/Monoclonal Antibody C225 Clinical Clinical Trials Combination Chemotherapy Data Deglutition Disorders Development Down-Regulation EGFR inhibition Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Extracellular Signal Regulated Kinases Foundations Future G1 Arrest Geldanamycin Goals HSP 90 inhibition Head and Neck Cancer Head and Neck Neoplasms Head and neck structure Heat-Shock Proteins 90 High Pressure Liquid Chromatography Immunoblotting Immunofluorescence Immunologic Institution Laryngectomy Laryngoscopy Larynx Literature MEKs Mediating Methods Molecular Molecular Chaperones Morbidity - disease rate Mucositis Numbers Operative Surgical Procedures Organ Organ Preservation Organ Survival Outcome Pathway interactions Patient Selection Patients Phase Phase II Clinical Trials Phosphoproteins Play Postoperative Period Proteins Proteomics Protocols documentation Radiation Radiation Tolerance Radiation therapy Radiosensitization Rate Resistance Role Schedule Selection for Treatments Signal Transduction Signal Transduction Pathway Silicon Dioxide Specimen Techniques Technology Testing Tissue Microarray Toxic effect Treatment Protocols Week Xenograft procedure base cell killing chemotherapy cytotoxicity day design experience improved inhibitor/antagonist neoplastic cell novel novel strategies pre-clinical preclinical study response tumor

项目摘要

The development of organ-conserving treatment for locally advanced head and neck cancers shifted the paradigm for treatment. A decade ago, we developed the strategy of selecting patients for chemoradiotherapy or for laryngectomy based on their response to a single cycle of chemotherapy. This approach results in 3-year cause-specific survival and laryngeal preservation rates of 87% and 70%, respectively. However, chemoradiation is associated with an increased rate of mucositis and dysphagia compared with radiotherapy alone. The long-term goal of this application is to preserve a high rate of larynx preservation while decreasing the toxicity of treatment by using cetuximab-radiation instead of chemoradiotherapy in patients selected to benefit from this approach. These goals will be achieved through 3 specific aims. Specific Aim 1 is to decrease the toxicity of larynx-preserving treatment by using cetuximab-radiation in place of chemoradiation in appropriately selected patients. In Aim 1A we propose to extend our current strategy in a phase II study of cetuximab-radiation for patients who would previously have received chemoradiation: those responding to a cycle of chemotherapy. In Aim 1B, we propose to assess tumor biopsies in the patients who respond to a cycle of chemotherapy and then receive cetuximab for markers of EGFR activation and downstream inhibition as possible predictors of response to cetuximab-radiation. Specific Aim 2 is to investigate the potential of established markers (Aim 2A) and to discover potential new biomarkers (Aim 2B) by assessment of phosphoproteome to predict response to cetuximab combined with radiation. Our preliminary data suggest that the extent and duration of decrease in the established markers like total EGFR, pEGFR, pSTATS, Bcl-XL, and Ki67 correlate with response to the combination of EGFR inhibitors and radiation. In this aim, we propose to extend these studies to a total of 20 head and neck xenografts, 10 responsive and 10 non-responsive. In Aim 2B we will assess the effects of cetuximab-radiation on phosphoproteins using proteomic technology. Our preliminary data indicate that this is a promising method of identifying novel phosphoproteins that are affected by cetuximab treatment. Specific Aim 3 is to carry out preclinical studies to improve the efficacy of EGFR inhibition with radiochemotherapy. In Aim 3A, we focus on the potential importance of schedule for combining EGFR inhibition with radiochemotherapy. In Aim 3B we will focus on a novel approach toward targeting EGFR via HSP90 inhibition. Our preliminary data show that geldanamycin, an inhibitor of HSP90, accelerates the degradation of EGFR in cisplatin resistant cells, leading to both cellular toxicity and radiosensitization. We feel our preclinical and clinical team with an extensive track record in this field makes it likely that these studies will improve patient outcome.

针对本地高级头颈癌的器官持续处理的发展发生了变化治疗范式。十年前，我们制定了选择患者的策略化学放疗或喉切除术基于对单个化疗周期的反应。这方法导致3年特异性生存和喉部保存率为87％和70％，分别。但是，化学放疗与粘膜炎和吞咽困难率升高有关与仅放射疗法相比。该应用的长期目标是保持高率喉部保存，同时使用西妥昔单抗辐射降低治疗的毒性被选为从这种方法中受益的患者的化学放射疗法的。这些目标将是通过3个特定目标实现。具体目的1是降低喉部含量的毒性通过在适当选择的患者中使用西妥昔单抗辐射代替化学放疗的治疗。在AIM 1A中，我们建议在针对患者的西妥昔单抗降射研究中扩展当前策略以前会接受化学放疗的人：那些对化学疗法循环的反应。目标 1B，我们建议评估对化学疗法反应的患者的肿瘤活检，然后接受西妥昔单抗，以作为EGFR激活和下游抑制的标志物作为可能的预测指标对西妥昔单抗辐射的反应。具体目标2是研究既定标记的潜力（AIM 2A），并通过评估磷蛋白质组来发现潜在的新生物标志物（AIM 2B）预测对西妥昔单抗的反应与辐射结合。我们的初步数据表明程度以及已建立标记的持续时间，例如总EGFR，PEGFR，PSTATS，BCL-XL和KI67 与响应EGFR抑制剂和辐射的响应相关。在这个目标中，我们建议将这些研究扩展到总共20个头和颈部异种移植物，10个反应性和10个无反应性。在 AIM 2B我们将使用蛋白质组学技术评估西妥昔单抗辐射对磷酸蛋白的影响。我们的初步数据表明，这是鉴定新型磷蛋白的一种有前途的方法受西妥昔单抗治疗的影响。具体目标3是进行临床前研究以改善通过放射化学疗法抑制EGFR的功效。在AIM 3A中，我们专注于潜在的重要性 EGFR抑制与放射化学疗法相结合的时间表。在AIM 3B中，我们将专注于小说通过HSP90抑制靶向EGFR的方法。我们的初步数据表明，Geldanamycin，一个 HSP90的抑制剂，加速了eGFR在顺铂耐药细胞中的降解，导致两种细胞毒性和放射敏化。我们感受到了我们的临床前和临床团队，并具有广泛的往绩该领域使这些研究可能会改善患者的结果。