Molecular features impacting drug resistance in atypical EGFR exon 18 and exon 20 mutant non-small cell lung cancers and the development of novel mutant-selective inhibitors
影响非典型 EGFR 外显子 18 和外显子 20 突变非小细胞肺癌耐药性的分子特征以及新型突变选择性抑制剂的开发
基本信息
- 批准号:10593969
- 负责人:
- 金额:$ 56.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdverse eventAffinityBindingCancer PatientClassificationClinicalClinical DataCrystallographyDataDevelopmentDiarrheaDoseDrug KineticsDrug ScreeningDrug resistanceERBB2 geneEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEvaluable DiseaseExanthemaExonsFDA approvedGenerationsGenetically Engineered MouseIn VitroLaboratory ScientistsLibrariesMalignant NeoplasmsMedicineModelingMolecularMutationNatureNon-Small-Cell Lung CarcinomaPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhysiciansPopulationProgression-Free SurvivalsReceptor InhibitionReportingResearch PersonnelResistanceResourcesRetrospective StudiesSpecificityStructural BiologistStructure-Activity RelationshipSubgroupTestingTherapeutic AgentsToxic effectTranslatingTyrosine Kinase InhibitorWorkdesignexperienceimprovedin silicoin vivoinhibitorinsightinterdisciplinary approachmolecular dynamicsmolecular modelingmultidisciplinarymutantnovelobjective response ratepatient derived xenograft modelphase II trialpre-clinicalpreventrational designreceptorresearch clinical testingresponsetumor
项目摘要
PROJECT SUMMARY
Approximately 20% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor atypical
mutations. Unlike NSCLC patients bearing “classical” EGFR mutations (L858R or exon 19 deletions), the patients
with atypical mutations in exon 18 or 20 are resistant to FDA-approved first-generation tyrosine kinase inhibitors
(TKIs), with exon 20 patients presenting response rates of only 4-8% and a median progression free survival
(mPFS) of 2 months based on retrospective studies. Similarly, patients with atypical EGFR exon 18 mutations
have less clinical benefit than patients with classical EGFR mutations when treated with common EGFR- TKIs.
The population impacted by atypical EGFR NSCLC mutations is sizable: approximately 5,000 patients per year
in the US, 41,600 patients per year worldwide, and an even greater number of patients outside of NSCLC. We
recently reported the results of a detailed structural and functional analysis that led to the identification of the
TKI, poziotinib, as a potent and clinically active inhibitor of EGFR and HER2 exon 20 mutant tumors. Based on
this data we have conducted an investigator-initiated phase II trial testing poziotinib in EGFR and HER2 exon 20
mutant NSCLC patients, demonstrating that it is highly active drug for with confirmed objective responses
observed in 43% of patients. This clearly represents an advance for these patients, however, the drug has
significant limitations. Responses to poziotinib treatment were of limited duration, with a mPFS of 5.5 months,
and even less activity was observed in patients with mutations in the “far loop” of exon 20. Whereas patients
with classical EGFR mutations have a mPFS of 18.9 months to osimertinib. Furthermore, many patients receiving
poziotinib experienced >grade 3 adverse events, diarrhea and rash, related to the activity of this drug against
wild-type EGFR, resulting in dose reduction in >60% of patients. To address these limitations, we propose an
integrative analysis to understand the structural features of EGFR exon 18 and 20 mutations, so that more potent
inhibitors can be developed and that specificity for mutant to WT receptor can be enhanced. To achieve this, we
propose the following aims: Aim 1) we will study the structural features of EGFR exon 20 mutations that drive
differential sensitivity to TKIs to guide the development of novel compounds with increased potency. Aim 2) we
will analyze the structural features of atypical EGFR exon 18 mutations to use this information to rationally design
new compounds with enhance efficacy. Aim 3) we will develop novel TKIs with improved EGFR mutant vs wild-
type specificity to augment drug tolerability and clinical benefit of EGFR exon 18 and exon 20 mutant patients.
We have assembled a unique, multi-disciplinary team of physicians, laboratory scientist, structural biologist, and
medicinal chemists with unparalleled pre-clinical and clinical resources for who will work cooperatively to gain
insights into the structural features of EGFR exon 18 and 20 mutant cancers and to translate this into preclinical
and potentially clinical testing. Furthermore, insights gained from this study can help to accelerate efforts
worldwide aiming to target EGFR exon 18 and 20 tumors as well as other EGFR mutant caners.
项目摘要
EGFR突变的非小细胞肺癌(NSCLC)患者约有20%具有非典型
与带有“经典” EGFR突变的NSCLC患者不同(L858R或外显子19删除)
外显子18或20中具有非典型突变对FDA批准的第一基因酶激酶抑制剂具有抗性
(TKI),外显子20患者的前响应率仅为4-8%,并且中位程序进展无生存率
基于回顾性研究的2个月的(MPF)。
与经典EGFR突变患者相比,用普通EGFR-TKI治疗的临床益处较小。
受非典型EGFR NSCLC突变影响的人口大小:每年约5,000名患者。
在美国,全球珀斯(Perth)的41,600年,以及NSCLC以外的更多患者
最近报道了导致您识别的详细结构和功能分析的结果
tki,Poziotinib,是基于EGFR和HER2 20突变肿瘤的有效和临床活动
这些数据我们已经进行了研究人员发起的II期试验测试,对EGFR和HER2 20 20进行了研究
突变的NSCLC患者,证明它是具有确认客观反应的高度活性药物
在43%的患者中观察到。
对Poziotinib治疗的重大局限性是持续时间有限的,MPF为5.5个月
在外显子20的“远循环”中突变的患者中观察到的活性甚至更少。
经典的EGFR突变的MPF为18.9个月,到Osimertinib。
poziotinib经历了> 3年级不良事件,腹泻和皮疹,与该药物的活性有关
野生型EGFR,导致> 60%的患者的剂量减少。
综合分析以了解EGFR外显子18和20突变的结构特征,以便更有效
可以开发抑制剂,并且可以增强对WT受体的特异性。
提出以下目的:目标1)我们将研究EGFR外显子20突变的结构特征
对TKI的差异敏感性指导效力增加的新化合物的发展
将分析非典型EGFR外显子18突变的结构特征,以合理设计这些信息
具有增强功效的新化合物。
EGFR外显子18和Exon 20突变患者增强药物耐受性和临床益处的类型特异性。
我们组建了一个唯一的唯一学科团队,由医师,实验室科学家,结构生物学家和
具有未平行的前临床和临床资源的药物学家,谁可以获得Wilk合作社
洞悉EGFR外显子18和20突变体癌的结构特征,并将其转化为临床前
并可能进行临床测试。
全球旨在以其他EGFR突变罐作为EGFR外显子18和20肿瘤。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John V. Heymach其他文献
John V. Heymach的其他文献
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{{ truncateString('John V. Heymach', 18)}}的其他基金
Molecular features impacting drug resistance in atypical EGFR exon 18 and exon 20 mutant non-small cell lung cancers and the development of novel mutant-selective inhibitors
影响非典型 EGFR 外显子 18 和外显子 20 突变非小细胞肺癌耐药性的分子特征以及新型突变选择性抑制剂的开发
- 批准号:
10377501 - 财政年份:2020
- 资助金额:
$ 56.65万 - 项目类别:
Therapeutic strategies against EGFR exon 20 mutant lung cancer
EGFR外显子20突变肺癌的治疗策略
- 批准号:
10530622 - 财政年份:2019
- 资助金额:
$ 56.65万 - 项目类别:
Therapeutic strategies against EGFR exon 20 mutant lung cancer
EGFR外显子20突变肺癌的治疗策略
- 批准号:
10062900 - 财政年份:2019
- 资助金额:
$ 56.65万 - 项目类别:
Therapeutic strategies against EGFR exon 20 mutant lung cancer
EGFR外显子20突变肺癌的治疗策略
- 批准号:
10304886 - 财政年份:2019
- 资助金额:
$ 56.65万 - 项目类别:
Therapeutic strategies against EGFR exon 20 mutant lung cancer
EGFR外显子20突变肺癌的治疗策略
- 批准号:
9885320 - 财政年份:2019
- 资助金额:
$ 56.65万 - 项目类别:
Therapeutic approaches for LKB1-deficient non-small cell lung cancer
LKB1缺陷型非小细胞肺癌的治疗方法
- 批准号:
9890784 - 财政年份:2016
- 资助金额:
$ 56.65万 - 项目类别:
Markers and therapeutic strategies for overcoming chemoradiotherapy resistance
克服放化疗耐药性的标志物和治疗策略
- 批准号:
8703513 - 财政年份:2011
- 资助金额:
$ 56.65万 - 项目类别:
Markers and therapeutic strategies for overcoming chemoradiotherapy resistance
克服放化疗耐药性的标志物和治疗策略
- 批准号:
8332452 - 财政年份:2011
- 资助金额:
$ 56.65万 - 项目类别:
Markers and therapeutic strategies for overcoming chemoradiotherapy resistance
克服放化疗耐药性的标志物和治疗策略
- 批准号:
8509639 - 财政年份:2011
- 资助金额:
$ 56.65万 - 项目类别:
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