Translational Assess. of Kinase Targets in Lung Cancer

描述(由申请人提供)：这项拨款申请的总体目标是支持发展专注于建立基于转化/临床机制的抗癌药物开发的指导职业。这包括理解实验室靶标验证和临床药物开发的概念，重点是在早期临床试验中使用基于实验室的相关研究。为了实现这一目标，我们将重点研究针对ErbB受体家族的药物对实体瘤患者特别是非小细胞肺癌(NSCLC)患者受体磷酸化和下游PI3K/AKT、MAPK和JAK/STAT通路激活的影响。目的：比较未治疗的非小细胞肺癌中EGFR的磷酸化和下游效应蛋白(p-MAPK、p-AKT、p-STAT3)的磷酸化与总表达的预后价值。这将通过对200例手术切除的NSCLC患者进行总的和磷酸化的EGFR、MAPK、AKT和STAT3的免疫组织化学分析来完成。目的：确定抑制EGFR和下游靶点STAT-3在体内是否具有相加的抗增殖活性。我们在体外已经证实，针对A431细胞中的EGFR和JAK/STAT通路的药物联合使用比单独使用药物具有更好的生长抑制效果。这一目标的完成将证明在过度表达EGFR的肿瘤异种移植模型中，阻断EGFR和JAK/STAT通路的策略是否比单一药物更有效。目的3：在一项I期试验中，确定靶向ErbB受体的GW572016是否能减少EGFPJErbB2的磷酸化，并减少肿瘤组织中下游效应蛋白(AKT、MAPK、STAT3)的激活。将获得连续的肿瘤活组织检查。这项试验将确定这种EGFR/erb-B2的小分子双重抑制剂是否影响其目标受体激活和人类肿瘤组织中下游效应蛋白，它还将确定晚期实体肿瘤患者的最佳生物剂量(影响受体激活所需的最小剂量)。目的：在一项II期临床试验中，测定GW572016(双EGFPJErbB2抑制剂)治疗非小细胞肺癌的疗效(有效率)。根据我们的临床前数据，与单独使用EGFR相比，靶向EGFR和ErbB2的抗肿瘤活性更好。

DESCRIPTION (provided by applicant): The overall goal of this grant application is to support the development of a mentored-career that focuses on building a foundation of translational/clinical mechanism-based anticancer drug development. This includes understanding the concept of target validation in the laboratory and drug development in the clinic with emphasis on the use of laboratory-based correlative studies during early phase clinical trials. To achieve this goal, we will focus on the effects of agents targeting the ErbB receptor family on receptor phosphorylation and the activation of downstream PI3K/AKT, MAPK, and JAK/STAT pathways in patients with solid tumors with special emphasis on non-small cell lung cancer (NSCLC). Aim 1: We will determine the prognostic value of EGFR phosphorylation and phosphorylation of downstream effector proteins (p-MAPK, p-AKT, p-STAT3) in comparison to total expression of these proteins in untreated NSCLC. This will be done by performing immunohistochemical analysis of 200 surgically resected NSCLC patients for both total and phosphorylated EGFR, MAPK, AKT and STAT3. Aim 2: To establish whether inhibition of both EGFR and downstream target STAT-3 have additive anti-proliferative activity in vivo. We have established in vitro that the combination of agents targeting EGFR and the JAK/STAT pathways in A431 cells have superior growth inhibitory effects in combination as opposed to single agents. Completion of this aim will demonstrate if strategies to block EGFR and JAK/STAT pathways are more effective than single agents in tumor xenograft models overexpressing EGFR. Aim 3: Determine in a phase I trial if treatment with GW572016, an agent targeting ErbB receptors, decreases EGFPJErbB2 phosphorylation and reduces activation of downstream effector proteins (AKT, MAPK, STAT3) within tumor tissue. Sequential tumor biopsies will be obtained. This trial will establish if this small molecule dual inhibitor of EGFR/erb-B2 effects its target receptor activation and downstream effector proteins in human tumor tissue and it will also establish the optimal biological dose (minimal dose required to effect receptor activation) in patients with advanced solid tumors. Aim 4:To determine the efficacy (response rate) of GW572016 (dual EGFPJErbB2 inhibitor) in NSCLC during a phase II clinical trial. Based on our preclinical data targeting EGFR and ErbB2 results in superior anti-tumor activity as compared to EGFR blockade alone.