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。Erlotinib （Tarceva, 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，在难治性NSCLC患者中显示出延长生存期和非常耐受的毒性。如果能够根据患者对厄洛替尼的敏感性和/或耐药性的肿瘤分子决定因素成功选择患者，则厄洛替尼的结果将显著改善。本提案的主要目的是确定新切除的非小细胞肺癌肿瘤异源移植裸鼠作为非小细胞肺癌临床相关模型对厄洛替尼敏感/耐药的决定因素。正在测试的广泛假设是，对厄洛替尼的敏感性需要肿瘤对EGFR轴的生长和/或存活的依赖性，而对厄洛替尼的耐药性是由替代信号转导途径的激活引起的。具体目标是：1。建立裸鼠移植的人非小细胞肺癌肿瘤文库，并评价移植肿瘤与患者原发肿瘤的遗传相似性。2. 2 .确定厄洛替尼在NSCLC异源移植中的抗肿瘤活性，确定肿瘤反应、疾病稳定和肿瘤进展的分子决定因素，并开发一种包括临床和分子参数的数学算法，以计算个体患者接受厄洛替尼治疗后肿瘤反应/进展的概率；为了确认该算法在一组化疗耐药NSCLC患者中的预测价值，这些患者被选中的原因是他们接受单药厄洛替尼治疗获得缓解或疾病稳定的可能性很大。

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.