Unmet needs for specific subsets of EGFR mutated lung cancer

EGFR 突变肺癌特定亚型的需求未得到满足

基本信息

批准号：
10328512
负责人：
Daniel Botelho Costa
金额：
$ 40.05万
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：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328512
关键词：
Adenosine Kinase Adenosine Triphosphate Affinity Amino Acids Antibodies Apoptosis Apoptotic Binding Biology Cancer Etiology Cell Death Cell Line Cessation of life Clinical Clinical Trials Collection Combined Modality Therapy Data Development Disease Dose Drug Design EGFR gene ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Exons Future Gefitinib Generations Genetically Engineered Mouse Genomics Genotype Goals Insertion Mutation Kinetics Liquid substance Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mitochondria Modeling Morbidity - disease rate Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Outcome Palliative Care Pathway interactions Patient Care Patients Phosphotransferases Point Mutation Pre-Clinical Model Precision therapeutics Quality of life Reporting Research Resistance Scheme Signal Transduction Structure Subgroup Testing Therapeutic Therapeutic Index Tissues Translating Tyrosine Kinase Inhibitor United States Woman Xenograft procedure antitumor effect base cancer therapy clinical care clinical development clinical efficacy cohort confirmatory clinical trial driver mutation effective therapy erbB-2 Receptor experimental study improved in vivo Model inhibitor therapy insertion/deletion mutation kinase inhibitor men mortality mutant novel novel therapeutics oncogene addiction pre-clinical prevent radiological imaging rational design refractory cancer resistance mechanism response translational goal tumor

项目摘要

ABSTRACT/PROJECT SUMMARY Lung cancer is the leading cause of cancer-related mortality for both men and women in the United States. The number of new cases of lung cancer exceeds 220,000 yearly; with an appalling five year survival of 16% for non-small-cell lung cancer (NSCLC). The overall goal of the proposed research is to decrease suffering and improve survival for NSCLCs harboring epidermal growth factor receptor (EGFR, ErbB1) or ERBB2 mutations (i.e., >20% of all NSCLCs; the most common cause of cancer death worldwide). EGFR mutated NSCLCs comprise diseases with a distinct biology marked predominantly by targetable mutations involving inframe indels in exon 19 and the point mutation L858R. Some tyrosine kinase inhibitors (TKIs) can effectively inhibit signaling from these aberrant kinases, disrupt their downstream signaling cascades and induce apoptosis. TKIs are now clinically available (gefitinib, erlotinib, afatinib and osimertinib) or in development as palliative therapies for advanced EGFR mutated NSCLC. However, the third most prevalent group of EGFR mutations in NSCLC (>10% of cases) is composed of inframe insertions (of 1-4 amino-acids spanning residues E762 to C775) within exon 20 of EGFR that are insensitive to approved EGFR TKIs. Therefore, the identification of therapies that can or not abrogate kinase activity for EGFR exon 20 insertion mutated NSCLCs are essential to understand the promises plus limitations of precisions therapies for this cohort of tumors. The close homology of EGFR and ErbB2 insertion mutations highlights that future therapeutic options for EGFR exon 20 insertion mutations will be applicable to other cohorts of NSCLC. The proposal will take advantage of our budding comprehensive models to completely characterize EGFR exon 20 mutants and identify novel therapies for this genomic subgroup of tumors. Aim 1 will establish robust preclinical models to represent EGFR exon 20 insertion mutations as a homogenous group; with a goal of generating novel models that are necessary to evaluate therapies against these NSCLCs. Aim 2 will evaluate available and novel therapies against EGFR exon 20 mutants; with a goal of identifying effective therapies - including EGFR/ERBB2 exon 20 mutant specific TKIs – and their putative mechanisms of resistance. Aim 3 will support the clinical development of an EGFR/ERBB2 exon 20 mutant specific TKI; with a goal of confirming the clinical efficacy of such a class of drugs and designing rational combination therapies to prevent the development of acquired resistance. The final translational goals of these models are to provide rational concepts that can be explored initially in confirmatory clinical trials and subsequently in the clinical care of patients. If these goals are met, quality of life and survival of patients will be extended beyond what is currently available.

摘要/项目摘要肺癌是美国男性和女性癌症相关死亡的主要原因。每年新增肺癌病例数超过 220,000 例，五年生存率高达 16%，令人震惊；拟议研究的总体目标是减少非小细胞肺癌（NSCLC）的痛苦和治疗。提高携带表皮生长因子受体（EGFR、ErbB1）或 ERBB2 突变的 NSCLC 的生存率（即，>20% 的 NSCLC；全球 EGFR 突变 NSCLC 的最常见癌症死亡原因）。包含具有独特生物学特征的疾病，主要以涉及框内的靶向突变为特征外显子 19 的 indels 和点突变 L858R 一些酪氨酸激酶抑制剂 (TKI) 可以有效抑制。来自这些异常激酶的信号传导，破坏其下游信号级联并诱导细胞凋亡。 TKI 现已投入临床使用（吉非替尼、厄洛替尼、阿法替尼和奥希替尼）或正在开发作为姑息治疗药物晚期 EGFR 突变 NSCLC 的治疗方法然而，第三组最常见的 EGFR 突变。 NSCLC（>10% 的病例）由框内插入（1-4 个氨基酸跨越残基 E762 至 C775）位于 EGFR 外显子 20 内，对已批准的 EGFR TKI 不敏感，因此需要鉴定。能够或不能消除 EGFR 外显子 20 插入突变 NSCLC 激酶活性的疗法对于了解针对这组肿瘤的精准治疗的前景和局限性。 EGFR 和 ErbB2 插入突变凸显了 EGFR 外显子 20 插入的未来治疗选择突变将适用于其他非小细胞肺癌队列。该提案将利用我们的萌芽。全面表征 EGFR 外显子 20 突变体并确定新疗法的综合模型目标 1 将建立代表 EGFR 外显子 20 的稳健临床前模型。插入突变作为同质组；目标是生成必要的新模型评估针对这些 NSCLC 的疗法，目标 2 将评估针对 EGFR 的现有疗法和新型疗法。外显子 20 突变体；目标是确定有效的治疗方法 - 包括 EGFR/ERBB2 外显子 20 突变体目标 3 将支持特定 TKI 的临床开发。 EGFR/ERBB2 外显子 20 突变特异性 TKI；目的是确认此类药物的临床疗效合理设计联合疗法以防止获得性耐药的发展。这些模型的最终转化目标是提供可以在以下方面进行初步探索的理性概念：如果这些目标得到实现，患者的生活质量将得到验证性临床试验和随后的临床护理。患者的生存期将超过目前的水平。