Overcoming acquired resistance to EGFR inhibitors in lung cancer

克服肺癌对 EGFR 抑制剂的获得性耐药

基本信息

批准号：
8237311
负责人：
WILLIAM PAO
金额：
$ 30.26万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237311
关键词：
Aftercare Antibodies Biochemical Cancer Biology Cell Line Cetuximab Clinical Trials Development Disease Disease Progression Drug Combinations Drug-sensitive Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Exons Funding Gefitinib Gene Amplification Generations Goals Grant Human Knowledge Ligands Lung Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Molecular Analysis Mutation Patients Phase Phosphotransferases Play Pre-Clinical Model Progressive Disease Protein Tyrosine Kinase Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Resistance Resistance development Role Signal Pathway Site Specimen Techniques Testing Tissues Transgenic Mice Tumor Tissue Tyrosine Kinase Domain Work Xenograft procedure base cancer cell cohort design experience improved insight mouse model mutant neoplastic cell novel pre-clinical receptor internalization resistance mechanism response therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva). However, after about one year, these patients develop progression of disease. No targeted therapy has proven clinically effective in treating acquired resistance. In the previously funded period, we identified several mechanisms of acquired resistance, including second-site EGFR mutations (>50% of cases) and amplification of the gene encoding the MET tyrosine kinase (up to 20% of cases). Using mouse models of lung cancer that we generated and characterized, we also showed that the most common form of resistance, mediated by the EGFR T790M mutation, could be overcome by a novel combination of the second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB/II clinical trial of this combination in humans has now shown unprecedented activity in this patient cohort with a 36% (8 of 22) radiographic response rate. However, at least one patient on this combination has already developed progressive disease, and surprisingly, some tumors without T790M have also responded. The overall goals of this revised proposal are to use human tumor specimens and cell lines, genetically engineered and xenograft mouse models, and various molecular and biochemical techniques to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases. PUBLIC HEALTH RELEVANCE: A new clinical trial involving two targeted agents (afatinib plus cetuximab) was rationally designed based upon findings from our previous funding period and has now shown unprecedented anti-tumor activity in patients with acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer. The goal of this grant is to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.

描述（由申请人提供）：超过 70% 的肺癌患者在编码表皮生长因子受体 (EGFR) 酪氨酸激酶结构域的外显子中存在特定突变，并对选择性 EGFR 酪氨酸激酶抑制剂 (TKI) 吉非替尼产生放射学反应（易瑞莎）或厄洛替尼（特罗凯）。然而，大约一年后，这些患者的疾病出现进展。目前还没有临床证明靶向治疗可有效治疗获得性耐药。在之前的资助期间，我们确定了获得性耐药的几种机制，包括第二位点 EGFR 突变（> 50% 的病例）和编码 MET 酪氨酸激酶的基因扩增（高达 20% 的病例）。使用我们生成和表征的肺癌小鼠模型，我们还表明，由 EGFR T790M 突变介导的最常见的耐药形式可以通过第二代 EGFR TKI 阿法替尼 (BIBW2992)、以及抗 EGFR 抗体西妥昔单抗。这种组合在人体中进行的 IB/II 期临床试验现已在该患者队列中显示出前所未有的活性，放射学反应率为 36%（22 人中的 8 人）。然而，至少一名接受这种联合治疗的患者已经出现了进展性疾病，令人惊讶的是，一些没有 T790M 的肿瘤也出现了反应。该修订提案的总体目标是使用人类肿瘤标本和细胞系、基因工程和异种移植小鼠模型以及各种分子和生化技术来进一步了解携带肺癌的 EGFR 突变体子集，这些突变体对 EGFR 抑制产生了获得性耐药性。对获得性耐药性的进一步了解有望使我们能够治疗/抑制进行性疾病的发展，并为 EGFR 或其他突变受体酪氨酸激酶驱动的癌症生物学提供新的见解。公共健康相关性：一项涉及两种靶向药物（阿法替尼加西妥昔单抗）的新临床试验是根据我们之前资助期的研究结果合理设计的，现已在对 EGFR 酪氨酸激酶抑制剂获得性耐药的肺癌患者中显示出前所未有的抗肿瘤活性。这笔资助的目的是进一步了解携带肺癌的 EGFR 突变体子集，这些突变体对 EGFR 抑制产生了获得性耐药性。对获得性耐药性的进一步了解有望使我们能够治疗/抑制进行性疾病的发展，并为 EGFR 或其他突变受体酪氨酸激酶驱动的癌症生物学提供新的见解。