P1 - Intersection of Estrogen Receptor Signaling & EGF Receptor

项目一将研究雌激素受体（ER）和表皮生长因子受体（EGF） （EGFR）激活非小细胞肺癌（NSCLC）中的增殖信号通路，并且这些 信号通路重叠并相互作用。根据在第一个SPORE资助期内取得的成果，我们 假设ER表达和信号传导在NSCLC中具有功能意义， ER和EGFR在NSCLC中可能显示出比单独抑制任一途径更大的抗肿瘤活性。数据 在第一个SPORE资助期获得的结果表明，ER途径可能存在一些性别差异， 但是ER通路在男性中也很活跃。我们将进行这项转化研究 该项目针对ER和EGFR有四个具体目标：（1）确定参与ER和EGFR的信号分子。 NSCLC细胞系中的ER-EGFR通路相互作用;（2）检查联合抑制EREGFR通路的有效性。 与使用临床相关药物的NSCLC单药治疗相比，肿瘤生长途径;（3） 确定芳香酶，合成雌激素的酶，是否存在和功能正常， 恶性肺细胞和芳香酶抑制剂是否具有抗肿瘤活性;和（4）分析ER和EGFR 在使用联合治疗的临床试验中从NSCLC患者获得的组织中的途径状态。结果 从这些目标将证明如何ER和EGFR信号通路相互作用，以及在何种程度上 配体依赖性和配体非依赖性ER信号传导在NSCLC增殖中起作用。结果也将 确定抑制雌激素合成是否是NSCLC的潜在有效治疗策略。 结果将进一步证明在临床试验中对ER和EGFR联合靶向的反应是如何影响的。 与患者肿瘤中的ER和EGFR信号通路相关，以及联合治疗是否 与单独靶向EGFR相比，具有上级临床应答。我们还将确定EGFR在多大程度上 在酪氨酸激酶结构域中具有突变的EGFR与野生型EGFR的不同之处在于ER的整合， EGFR通路。这些目标的实现将为靶向ER的治疗提供一个新的范例， NSCLC可适用于患有这种疾病的男性和女性。

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.