Determinants of Resistance to Erlotinib in NSCLC

描述（由申请人提供）：表皮生长因子信号转导通路在维持某些上皮恶性肿瘤（包括非小细胞肺癌（NSCLC））的生长和存活中起重要作用。厄洛替尼（特罗凯，OSI-774）是一种表皮生长因子受体（EGFR）酪氨酸激酶的选择性抑制剂，在一项随机III期临床研究中显示，它可延长难治性NSCLC患者的生存期，毒性特征非常耐受。如果患者能够根据其对该药物的敏感性和/或耐药性的肿瘤分子决定因素成功选择，则厄洛替尼的结果可以显著改善。本提案的主要目的是确定在作为临床相关NSCLC模型的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/耐药性的决定因素。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，并且对厄洛替尼的抗性是由替代信号转导途径的激活引起的。具体目标是：1.建立人非小细胞肺癌（NSCLC）裸鼠异种移植瘤库，并评估异种移植瘤与患者原发肿瘤之间的遗传相似性程度。2.确定厄洛替尼在非小细胞肺癌异移植中的抗肿瘤活性，确定肿瘤缓解、疾病稳定和肿瘤进展的分子决定因素，并开发包括临床和分子参数的数学算法来计算厄洛替尼治疗的肿瘤缓解/进展的可能性个体患者，和3.确认该算法在一组化疗耐药NSCLC患者中的预测价值，这些患者是根据厄洛替尼单药治疗获得缓解或疾病稳定的可能性高而选择的。

DESCRIPTION (provided by applicant): 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 sensitivity to 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.