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率的主要原因。这新的肺癌病例数超过22万年；以16％的惊人生存令人震惊非小细胞肺癌（NSCLC）。拟议研究的总体目标是减少痛苦和提高具有表皮生长因子受体（EGFR，ERBB1）或ERBB2突变的NSCLC的生存率（即，>，所有NSCLC的20％；全球癌症死亡的最常见原因）。 EGFR突变的NSCLC 包括具有涉及感染的可靶向突变，具有不同的生物学疾病外显子19和点突变L858R中的indels。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反应并诱导凋亡。 TKIS现在可以使用临床（gefitinib，erlotinib，afatinib和osimertinib）或开发为姑息晚期EGFR突变NSCLC的疗法。但是，第三大流行的EGFR突变组 NSCLC（> 10％的病例）由插入式插入（1-4个氨基酸含量跨越残差E762至 C775）在EGFR的外显子20中对批准的EGFR TKI不敏感。因此，识别可以或不清除EGFR外显子20插入突变NSCLC的激酶活性的疗法至关重要了解这种肿瘤队列的预期加上精确疗法的局限性。近距离同源 EGFR和ERBB2插入突变突出了EGFR外显子20插入的未来治疗选择突变将适用于其他NSCLC的同类。该提案将利用我们的萌芽综合模型以完全表征EGFR外显子20突变体并确定新的疗法肿瘤的基因组亚组。 AIM 1将建立强大的临床前模型来代表EGFR外显子20 插入突变作为同质组；以产生新型模型的目的评估针对这些NSCLC的疗法。 AIM 2将评估针对EGFR的可用疗法和新颖的疗法外显子20突变体；目的是识别有效的疗法 - 包括EGFR/ERBB2外显子20突变体特定的TKI及其推定的抵抗机制。 AIM 3将支持一个 EGFR/ERBB2外显子20突变体特异性TKI;目的是确认此类类别的临床效率药物和设计合理组合疗法以防止获得获得的抗性。这这些模型的最终翻译目标是提供合理的概念，最初可以探索这些概念确认性临床试验，随后在患者的临床护理中进行。如果实现这些目标，生活质量患者的生存将延长到目前可用的范围之外。