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：
8380699
负责人：
Jill M Siegfried
金额：
$ 17.98万
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/8380699
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.

头颈部鳞状细胞癌（SCCHN）的生长控制丧失的特征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批准了EGFR单克隆抗体西妥昔单抗治疗SCCHN，这使其成为45年内批准该癌症的首款新药。然而，尽管EGFR在SCCHN肿瘤中的无处不在表达，但作为单药治疗的西妥昔单抗的临床反应率受到限制。在EGFR阻断中与Cetuximab施用一起激活的致癌途径的共同定位可能会提高治疗益处。在上一个资金期间，该项目的重点是阐明SCCHN中G蛋白偶联受体（GPCR）（GPCR）之间的相互作用，其长期目标是设计针对头和颈部癌症患者的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。在没有临床使用的PAN-GPCR抑制剂的情况下，我们选择将该项目重新集中于SFK和EGFR在此更新应用中的共同定位。新的初步数据还暗示了在EGFR电阻或阻滞的情况下C-MET的激活。我们的工作假设是，在EGFR阻滞的情况下，通过替代激酶的持续信号传导有助于SCCHN中对EGFR靶向的临床反应有限。过度的假设是，有一些定义的替代途径绕过了癌细胞对EGFR信号的需求，并代表了联合治疗的潜在靶标。我们确定的两个候选人是SFK和C-MET。这些研究的完成将阐明对EGFR靶向策略的抗性机制，从而促进治疗方案的设计以增强临床反应。我们将通过确定：1）在EGFR抑制剂耐药性的SCCHN临床前模型中对EGFR和SRC家族激酶联合抑制的抗肿瘤机制； 2）HGF/C-MET信号传导在SCCHN对EGFR抑制和/或作为SCCHN治疗的替代靶标中的作用； 3）西妥昔单抗加上dasatinib在SCCHN患者中的治疗潜力。