Role of EGFR mutations and new therapeutics in lung cancer

EGFR 突变和新疗法在肺癌中的作用

基本信息

批准号：
7455166
负责人：
Susumu Kobayashi
金额：
$ 13.2万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7455166
关键词：
Accounting CL 387785 Cancer Etiology Cancer Patient Cessation of life Diagnosis Disease Effectiveness Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Future Gefitinib Goals Growth Lead Malignant neoplasm of lung Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Patients Resistance Role Running Staging Therapeutic Intervention Time Tyrosine Tyrosine Kinase Domain Tyrosine Kinase Inhibitor cancer diagnosis chemotherapy insight kinase inhibitor mutant novel novel strategies novel therapeutics response tumor

Accounting CL 387785 Cancer Etiology Cancer Patient Cessation of life Diagnosis Disease Effectiveness Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Future Gefitinib Goals Growth Lead Malignant neoplasm of lung Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Patients Resistance Role Running Staging Therapeutic Intervention Time Tyrosine Tyrosine Kinase Domain Tyrosine Kinase Inhibitor cancer diagnosis chemotherapy insight kinase inhibitor mutant novel novel strategies novel therapeutics response tumor

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项目摘要

DESCRIPTION (provided by applicant): Currently there will be an estimated 170,000 new cases of lung cancer diagnosed annually, and lung cancer will remain the leading cause of cancer deaths . The present treatment of locally advanced and metastatic lung cancer is very unsatisfactory, and the overall.5-year survival of patients diagnosed with lung cancer is only about 15%. The disappointing results of recent studies have led to the realization that we have reached a "chemotherapy efficacy plateau". A recent analysis of trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in the treatment of this disease. It has recently been shown that activating mutations in the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase domain determine responsiveness to the therapies utilizing EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, in Non-small cell lung cancer (NSCLC) patients. Despite the dramatic responses to the TKIs in certain subsets of NSCLC patients, resistance to the TKIs does emerge over time primarily due to a T790M secondary mutation in the tyrosine kinase domain. Whereas the T790M mutation likely accounts for half the tumors with acquired resistance to TKIs, other mechanism(s) by which resistance to the TKIs emerges are not known. In addition, although we have showed that an alternative, irreversible anilinoquinazoline EGFR inhibitor, CL-387,785, appears to overcome the resistance, new strategies of treatment are sorely needed, considering that novel resistant mutations against the irreversible EGFR inhibitors should occur in the long run and most of NSCLC patients are not curable unless the tumors are detected in an early-stage. Thus, our goals in this proposal are: 1) to clarify the mechanisms for the growth advantage of the T790M secondary mutation 2) to identify novel EGFR mutations in order to elucidate mechanisms of tyrosine kinase inhibitor resistance 3) to develop a novel therapy which could apply to NSCLC patients who do not respond to TKIs. These studies will lead to new insights into mutant EGFR-driven tumorgenesis, as well as the identification of novel target pathways for therapeutic intervention in the future.

描述（由申请人提供）：目前，估计每年被诊断出17万例新的肺癌病例，肺癌将仍然是癌症死亡的主要原因。目前对局部晚期和转移性肺癌的治疗方法非常不满意，总体总体治疗。诊断出患有肺癌的患者的5年生存率仅约15％。最近的研究结果令人失望的结果使我们意识到我们已经达到了“化学疗法疗效高原”。对过去30年中进行的试验的最新分析也清楚地表明，在治疗该疾病时仅取得了最小的进步。最近已经显示，表皮生长因子受体（EGFR）酪氨酸激酶结构域中激活突变决定了使用EGFR酪氨酸激酶抑制剂（TKIS），Gefitinib和Erlotinib，在非小细胞肺癌（NSCLC）患者中对疗法的反应性。尽管在NSCLC患者的某些子集中对TKI产生了巨大反应，但随着时间的推移，对TKIS的抗性确实是由于酪氨酸激酶结构域的T790M二次突变而出现的。尽管T790M突变可能是对TKI的耐药性的一半，而其他机制则是对TKIS抗性的其他机制。此外，尽管我们已经表明，一种替代性，不可逆的苯胺喹唑啉EGFR抑制剂CL-387,785似乎可以克服抗药性，但要考虑到新的耐药突变对长期以来的NSCLC不可逆性EGFR抑制剂的出现，并且在NSCLC不可避免的情况下会出现新的耐药性突变。因此，我们在该提案中的目标是：1）阐明T790M二次突变的生长优势的机制2）确定新型的EGFR突变，以阐明酪氨酸激酶抑制剂耐药性的机制3）开发一种新的治疗方法，该疗法适用于对TKIS不反应的NSCLC患者。这些研究将导致对突变EGFR驱动的肿瘤发生的新见解，以及对未来治疗干预的新目标途径的鉴定。