Determinants of Resistance to Erlotinib in NSCLC

表皮生长因子信号转导通路在维持表皮生长因子受体的表达中起重要作用。 某些上皮恶性肿瘤，包括非小细胞肺癌（NSCLC）的生长和存活。 厄洛替尼（Tarceva，OSI-774）是一种选择性表皮生长因子受体（EGFR）酪氨酸抑制剂， 在一项随机III期临床研究中， 难治性NSCLC和非常耐受的毒性特征。厄洛替尼的结果可以显著改善， 患者可以基于其敏感性的肿瘤分子决定因素和/或 抵抗这种药物。本建议的主要目的是确定 在裸鼠中异种移植的新鲜切除的NSCLC肿瘤中对厄洛替尼的敏感性/抗性， NSCLC的临床相关模型。正在测试的广泛假设是，对厄洛替尼的敏感性需要 肿瘤生长和/或存活对EGFR轴的依赖性，以及对厄洛替尼的耐药性， 是由信号传导途径激活引起的。具体目标是：1.开发一个 在裸鼠中异种移植的人NSCLC肿瘤的文库中，并评估基因表达的程度。 异源移植物和从患者切除的原发肿瘤之间的相似性。2.以确定 厄洛替尼在NSCLC异种移植中的抗肿瘤活性，以确定肿瘤的分子决定因素 反应，稳定的疾病和肿瘤进展，并开发一种数学算法，包括临床 和分子参数来计算厄洛替尼治疗的肿瘤反应/进展的概率， 个体患者和，3.为了证实该算法在一组患者中的预测价值， 选择化疗耐药NSCLC是因为其实现缓解或疾病稳定的可能性高， 单药厄洛替尼治疗。

The epidermal growth factor signal transduction pathway plays an important role in sustaining the growth and survival of certain epithelial malignancies, including non-small cell lung cancer (NSCLC). Erlotinib (Tarceva, OSI-774) is a selective inhibitor of the epidermal growth factor receptor (EGFR)tyrosine kinase that has shown prolongation of survival in a randomized Phase III clinical study in patients with refractory NSCLC and a very tolerable toxicity profile. Results with erlotinib could be markedly improved if patients could be successfully selected based on their tumor molecular determinants of sensitivity and/or resistance to this agent. The main objective of this proposal is to identify the determinants of sensitivity/resistance to erlotinib in freshly resected NSCLC tumors heterotransplanted in nude mice as clinically relevant models of NSCLC. The broad hypothesis being tested is that sensitivityto erlotinib requires a dependence of the tumor for growth and/or survival on the EGFR axis and that resistance to erlotinib is caused by activation of alternative signal transduction pathways. The specific aims are:1. To develop a library of human NSCLC tumors heterotransplanted in nude mice and to assess the degree of genetic similarity between the heterotransplants and the primary tumors resected from the patients. 2. To determine the antitumor activity of erlotinib in NSCLC heterotransplants, to identify molecular determinants of tumor response, stable disease, and tumor progression, and to develop a mathematical algorithm including clinical and molecular parameters to calculate the probability of tumor response/progression with erlotinib therapy in individual patients and,3. To confirm the predictive value of the algorithm in a group of patients with chemoresistant NSCLC selected for their high probability of achieving a response or stable disease with single agent erlotinib therapy.