Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases

EGFR 和 Src 家族激酶联合靶向的治疗机制

基本信息

批准号：
8541589
负责人：
Jill M Siegfried
金额：
$ 26.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8541589
关键词：
Address Biological Markers Bypass Cetuximab Clinical Clinical Trials Combined Modality Therapy Dasatinib Data Dose Enrollment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib FDA approved Funding G-Protein-Coupled Receptors Goals Growth Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma In Vitro Investigation Laboratories Ligands Malignant Neoplasms Mediating Modeling Molecular Target Monoclonal Antibodies Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phosphotransferases Pre-Clinical Model Primary Neoplasm Receptor Activation Receptor Inhibition Receptor Signaling Regimen Regulatory Pathway Reporting Resistance Role Signal Pathway Signal Transduction Solid Neoplasm Specialized Program of Research Excellence Squamous cell carcinoma Testing Therapeutic Tissues Up-Regulation Work autocrine cancer cell design efficacy testing head and neck cancer patient in vivo inhibitor/antagonist kinase inhibitor meetings pre-clinical receptor expression resistance mechanism response src-Family Kinases tumor tumorigenesis

项目摘要

The loss of growth control in squamous cell carcinoma of the head and neck (SCCHN) is characterized by acquisition of an autocrine regulatory pathway involving the epidermal growth factor receptor (EGFR). In 2006, the FDA approved the EGFR monoclonal antibody cetuximab for the treatment of SCCHN making it the first new drug approved for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited. Co-targeting of oncogenic pathways that are activated in the setting of EGFR blockade in conjunction with cetuximab administration may enhance therapeutic benefits. In the previous funding period, this project focused on elucidating interactions between G-protein-coupled receptors (GPCR) and EGFR in SCCHN with the long-term goal of designing a clinical trial combining EGFR and GPCR inhibitors for head and neck cancer patients. We demonstrated the critical role of Src family kinases (SFK) in GPCR-induced EGFR activation. In the absence of a pan-GPCR inhibitor for clinical use, we have elected to refocus this project on co-targeting of SFK and EGFR in this renewal application. New preliminary data also implicates activation of c-Met in the setting of EGFR resistance or blockade. Our working hypothesis is that persistent signaling through alternate kinases in the setting of EGFR blockade contributes to the limited clinical responses to EGFR targeting in SCCHN. The over-riding hypothesis is that there are defined alternative pathways that bypass a cancer cell's need for EGFR signaling, and represent potential targets for combination therapy. The two candidates we have identified are SFK and c-Met. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. We will accomplish this goal by determining: 1) the anti-tumor mechanisms of combined inhibition of EGFR and Src family kinases in SCCHN preclinical models of EGFR inhibitor resistance; 2) the role of HGF/c-Met signaling in mediating resistance of SCCHN to EGFR inhibition and/or as an alternative target for SCCHN therapy; and 3) the therapeutic potential of cetuximab plus dasatinib in SCCHN patients.

头颈鳞状细胞癌 (SCCHN) 生长失控的特点是获得了涉及表皮生长因子受体 (EGFR) 的自分泌调节途径。 2006年，FDA批准EGFR单克隆抗体西妥昔单抗用于治疗SCCHN，使其成为45年来第一个批准用于治疗这种癌症的新药。然而，尽管 EGFR 在 SCCHN 肿瘤中普遍表达，但西妥昔单抗作为单药治疗的临床反应率有限。联合靶向在 EGFR 阻断的情况下激活的致癌途径与西妥昔单抗联合给药可能会增强治疗效果。在之前的资助期间，该项目的重点是阐明SCCHN中G蛋白偶联受体（GPCR）和EGFR之间的相互作用，长期目标是设计针对头颈癌患者的结合EGFR和GPCR抑制剂的临床试验。我们证明了 Src 家族激酶 (SFK) 在 GPCR 诱导的 EGFR 激活中的关键作用。在缺乏临床使用的泛 GPCR 抑制剂的情况下，我们选择将这个项目的重点重新集中在本次更新应用中 SFK 和 EGFR 的共同靶向上。新的初步数据还表明 c-Met 在 EGFR 耐药或阻断的情况下被激活。我们的工作假设是，在 EGFR 阻断的情况下，通过替代激酶的持续信号传导导致 SCCHN 中 EGFR 靶向的临床反应有限。最重要的假设是，存在明确的替代途径，可以绕过癌细胞对 EGFR 信号传导的需求，并代表联合治疗的潜在靶点。我们确定的两个候选者是 SFK 和 c-Met。这些研究的完成将阐明 EGFR 靶向策略的耐药机制，从而有助于设计治疗方案以增强临床反应。我们将通过确定以下内容来实现这一目标：1）在 EGFR 抑制剂耐药的 SCCHN 临床前模型中联合抑制 EGFR 和 Src 家族激酶的抗肿瘤机制； 2) HGF/c-Met信号传导在介导SCCHN对EGFR抑制的抵抗和/或作为SCCHN治疗的替代靶点中的作用； 3) 西妥昔单抗联合达沙替尼对 SCCHN 患者的治疗潜力。