Intersection of Estrogen Receptor Signaling and Epidermal Growth Factor Receptor

雌激素受体信号传导与表皮生长因子受体的交叉点

基本信息

批准号：
7624396
负责人：
Jill M Siegfried
金额：
$ 27.53万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7624396
关键词：
A549 Adenocarcinoma Age Animals Antibodies Area Aromatase Aromatase Inhibitors Cancer Patient Cancer cell line Cell Line Cell Nucleus Cell Proliferation Cells Characteristics Clinical Clinical Trials Collaborations Combined Modality Therapy Cytoplasm Data Data Analyses Development Diagnosis Disease Doctor of Medicine Doctor of Philosophy Effectiveness Enrollment Enzymes Epidemiologic Studies Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Erlotinib Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Female Fibroblasts Fulvestrant Fulvestrant/Gefitinib Future Gefitinib Genomics Grant Head and Neck Cancer Head and neck structure Histologic Histology Hormonal Human Immunohistochemistry Incidence Individual Institution Investigation Joints Knowledge Laboratories Length Ligands Localized Lung Lung Neoplasms Malignant - descriptor Malignant neoplasm of lung Measurable Membrane Minority Molecular Weight Mutation Non-Small-Cell Lung Carcinoma Normal tissue morphology Outcome Paraffin Embedding Pathway interactions Patients Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Placebos Play Postmenopause Pre-Clinical Model Production Proteins Publishing Receptor Activation Receptor Signaling Reproduction spores Research Personnel Research Project Grants Resistance Role Sex Characteristics Signal Pathway Signal Transduction Signaling Molecule Small Cell Carcinoma Smoker Staging Structure of parenchyma of lung Supportive care Testing Testosterone Therapeutic Tissues Translational Research Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Universities University of Pittsburgh Cancer Institute Variant Woman Work anastrozole base c-erbB-1 Proto-Oncogenes cancer cell cell type clinically relevant head and neck cancer patient improved inhibitor/antagonist lung cancer prevention male men mutant neoplastic cell non-genomic novel pre-clinical programs protein function receptor receptor expression response sex size small molecule tumor tumor growth

项目摘要

Project One will examine the hypothesis that estrogen receptor (ER) and epidermal growth factor receptor (EGFR) activate proliferative signaling pathways in non-small cell lung cancer (NSCLC), and that these signaling pathways overlap and interact. Based on results obtained in the first SPORE grant period, we hypothesize that ER expression and signaling have functional significance in NSCLC and that co-inhibition of ER and EGFR may show greater anti-tumor activity in NSCLC than inhibition of either pathway alone. Data obtained in the first SPORE grant period suggest that there may be some sex differences in the ER pathway in lung cancer, but that the ER pathway is also active in males. We will carry out this translational research project targeting the ER and the EGFR in four specific aims: (1) Determine signaling molecules involved in ER-EGFR pathway interactions in NSCLC cell lines; (2) Examine effectiveness of joint inhibition of the EREGFR pathways on tumor growth compared to single therapy in NSCLC, using clinically relevant agents; (3) Determine if aromatase, the enzyme that synthesizes estrogen, is present and functional in normal and malignant lung cells and if an aromatase inhibitor has anti-tumor activity; and (4) Analyze ER and EGFR pathway status in tissues obtained from NSCLC patients on clinical trials using combination therapy. Results from these aims will demonstrate how the ER and EGFR signaling pathways interact and to what extent ligand-dependent and ligand-independent ER signaling play a role in NSCLC proliferation. Results will also determine whether inhibition of estrogen synthesis is a potentially effective therapeutic strategy for NSCLC. Results will further demonstrate how responses to combined ER and EGFR targeting in a clinical trial are related to ER and EGFR signaling pathways in patients' tumors and whether combined therapy gives superior clinical responses compared to targeting EGFR alone. We will also determine to what extent EGFR with mutation in the tyrosine kinase domain differs from wild type EGFR in the integration of the ER and EGFR pathways. Completion of these aims will provide a new paradigm for treatments targeting the ER in NSCLC that could be applied to both men and women with this disease.

项目一将检验雌激素受体（ER）和表皮生长因子受体的假设 (EGFR) 激活非小细胞肺癌 (NSCLC) 的增殖信号通路，并且这些信号通路重叠并相互作用。根据第一个 SPORE 资助期获得的结果，我们假设 ER 表达和信号传导在 NSCLC 中具有功能意义，并且共同抑制 ER 和 EGFR 在 NSCLC 中可能表现出比单独抑制任一途径更强的抗肿瘤活性。数据在第一个 SPORE 资助期内获得的结果表明 ER 途径可能存在一些性别差异 ER 通路在肺癌中也很活跃。我们将开展这项转化研究针对 ER 和 EGFR 的项目有四个具体目标：（1）确定参与的信号分子 NSCLC 细胞系中 ER-EGFR 通路的相互作用； (2) 检查联合抑制EREGFR的有效性使用临床相关药物与非小细胞肺癌单一疗法相比对肿瘤生长的影响途径； (3) 确定芳香酶（合成雌激素的酶）是否存在并在正常和正常状态下发挥作用恶性肺细胞以及芳香酶抑制剂是否具有抗肿瘤活性； (4) 分析 ER 和 EGFR 使用联合疗法的临床试验中从 NSCLC 患者获得的组织中的通路状态。结果这些目标将展示 ER 和 EGFR 信号通路如何相互作用以及相互作用的程度配体依赖性和配体非依赖性 ER 信号在 NSCLC 增殖中发挥作用。结果也将确定抑制雌激素合成是否是非小细胞肺癌的潜在有效治疗策略。结果将进一步证明临床试验中 ER 和 EGFR 联合靶向的反应如何与患者肿瘤中 ER 和 EGFR 信号通路相关以及联合治疗是否有效与单独靶向 EGFR 相比，具有更好的临床反应。我们还将确定 EGFR 达到什么程度酪氨酸激酶结构域突变的 EGFR 与野生型 EGFR 的不同之处在于 ER 和 EGFR 途径。这些目标的完成将为针对 ER 的治疗提供新的范例 NSCLC 可适用于患有这种疾病的男性和女性。