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

• 批准号: 10079470
• 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
• 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/10079470
• 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; Diagnostic radiologic examination; 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/antagonist; insertion/deletion mutation; kinase inhibitor; men; mortality; mutant; novel; novel therapeutics; oncogene addiction; pre-clinical; prevent; refractory cancer; resistance mechanism; response; tumor

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。这个 每年新发的肺癌病例超过22万例；令人震惊的五年生存率为16% 非小细胞肺癌(NSCLC)。拟议研究的总体目标是减少痛苦和 携带表皮生长因子受体(EGFR、ErbB1)或ERBB2突变的NSCLC提高存活率 (即，非小细胞肺癌占所有非小细胞肺癌的20%；是全球最常见的癌症死亡原因)。EGFR突变的非小细胞肺癌 包括具有不同生物学特征的疾病，其主要特征是涉及亚基酶的靶向突变 外显子19内含子和点突变L858R。一些酪氨酸激酶抑制剂(TKIs)可以有效地抑制 这些异常的激酶发出信号，干扰其下游信号级联反应，诱导细胞凋亡。 TKI现在可用于临床(吉非替尼、厄洛替尼、阿法替尼和奥西美替尼)或作为姑息性药物正在开发中 晚期EGFR突变非小细胞肺癌的治疗。然而，第三大最常见的EGFR突变组在 非小细胞肺癌(&gt；10%的病例)由基础插入(1-4个氨基酸组成，跨越残基E762至 对批准的EGFR TKIs不敏感的EGFR外显子20内的C775)。因此，识别出 能够或不能消除EGFR外显子20插入突变的非小细胞肺癌的激酶活性的治疗是必不可少的 了解精准疗法对这一肿瘤队列的承诺和局限性。紧密同调 EGFR和ErbB2插入突变的研究突显了未来EGFR外显子20插入的治疗选择 突变将适用于其他非小细胞肺癌队列。这项建议将利用我们的萌芽状态。 完整描述EGFR外显子20突变并确定其新疗法的综合模型 肿瘤的基因组亚群。目标1将建立稳健的临床前模型来代表EGFR外显子20 插入突变作为一个同源群体；目标是产生新的模式，这是必要的 评估针对这些非小细胞肺癌的治疗方法。AIM 2将评估针对EGFR的可用和新疗法 外显子20突变；目的是确定有效的治疗方法--包括EGFR/ERBB2外显子20突变 特定的TKI-及其推测的抗药性机制。AIM 3将支持AN的临床开发 EGFR/ERBB2外显子20突变的特异性TKI；目的是证实这种类型的临床疗效。 药物和设计合理的联合治疗，以防止获得性耐药的发展。这个 这些模型的最终翻译目标是提供可以在 验证性临床试验，随后在患者的临床护理中。如果实现了这些目标，生活质量 患者的存活期将延长到目前可用的范围之外。