Translational Assess. of Kinase Targets in Lung Cancer

描述（由申请人提供）：本资助申请的总体目标是支持指导职业的发展，重点是建立基于转化/临床机制的抗癌药物开发的基础。这包括理解实验室中的靶标验证和临床中的药物开发的概念，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，我们将重点关注靶向ErbB受体家族的药物对实体肿瘤患者中受体磷酸化和下游PI3K/AKT、MAPK和JAK/STAT通路激活的影响，特别是非小细胞肺癌（NSCLC）。目的1：我们将确定EGFR磷酸化和下游效应蛋白（p-MAPK, p-AKT, p-STAT3）磷酸化与未经治疗的NSCLC中这些蛋白的总表达的预后价值。这将通过对200例手术切除的非小细胞肺癌患者进行免疫组织化学分析，包括总EGFR、磷酸化的MAPK、AKT和STAT3。目的2：确定抑制EGFR和下游靶点STAT-3是否在体内具有附加的抗增殖活性。我们已经在体外建立了靶向EGFR和A431细胞中JAK/STAT通路的药物组合，与单一药物相比，联合使用具有更好的生长抑制效果。这一目标的完成将证明阻断EGFR和JAK/STAT通路的策略是否比单一药物在过表达EGFR的肿瘤移植模型中更有效。目的3：在I期试验中确定GW572016（一种靶向ErbB受体的药物）治疗是否能降低肿瘤组织中EGFPJErbB2磷酸化和下游效应蛋白（AKT， MAPK, STAT3）的激活。将进行序贯肿瘤活检。该试验将确定EGFR/ erbb - b2这种小分子双抑制剂是否在人肿瘤组织中影响其靶受体激活和下游效应蛋白，并将确定晚期实体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4：在II期临床试验中确定GW572016（双EGFPJErbB2抑制剂）治疗NSCLC的疗效（有效率）。根据我们的临床前数据，与单独阻断EGFR相比，靶向EGFR和ErbB2具有更好的抗肿瘤活性。

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.