Development of a first-in-class mEGFR dimerization inhibitor
开发一流的 mEGFR 二聚化抑制剂
基本信息
- 批准号:10778673
- 负责人:
- 金额:$ 33.35万
- 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:2020-04-03 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvanced DevelopmentAreaBindingBiodistributionBiological AvailabilityCancer PatientCancer cell lineCell DeathCell LineCell SurvivalCellsChronicClinicalClinical ResearchClinical effectivenessDataDevelopmentDiagnosisDimerizationDoseDrug ExposureDrug KineticsEffectivenessEpidermal Growth Factor ReceptorExposure toFrequenciesFutureGenerationsGenesGoalsImmunocompetentIn VitroKnowledgeLuciferasesLung NeoplasmsMalignant neoplasm of lungMethodsModelingMonitorMusMutateMutationNon-Small-Cell Lung CarcinomaNormal CellNull LymphocytesOncogenicOralOral AdministrationOrganPatient-Focused OutcomesPatientsPatternPharmaceutical PreparationsPharmacodynamicsPhosphotransferasesPlasmaPositron-Emission TomographyProbabilityProgression-Free SurvivalsProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesRegimenResearch DesignResistanceResistance developmentSafetyScheduleSeriesSpecificityStatistical ModelsStudy modelsTherapeuticTissuesToxic effectTreatment EfficacyTreatment ProtocolsTyrosine Kinase InhibitorXenograft ModelXenograft procedurecancer cellcancer imagingcancer therapychemotherapyclinically relevantdesignefficacy evaluationimproved outcomein vivoin vivo evaluationinhibitorinhibitor therapylung cancer celllung xenograftmouse modelmutantneoplastic cellnovelpatient derived xenograft modelpharmacokinetics and pharmacodynamicspre-clinicalprotein expressionreceptorreceptor expressionrefractory cancerresistance mutationresponsesmall moleculetargeted agenttherapy resistanttreatment effecttreatment responsetumortumor progression
项目摘要
Background: Lung cancers are often driven by mutant epidermal growth factor receptor (mtEGFR). While
EGFR tyrosine kinase activity inhibitors (TKI) have shown effectiveness, within 9-13 months all patients
develop resistance including to 3rd generation TKI - Osimertinib. These patients do not have any approved
therapy options, therefore, there is an urgent need to develop a novel agent that functions independently of
kinase function. DGD1202, a first-in-class, novel, orally bioavailable, small molecule that inhibits EGFR
dimerization, induces degradation of EGFR and selectively kills TKI resistant NSCLC tumors.
Objective: We and others have shown that the degradation of mutant EGFR protein has a profound effect on
cancer cell survival. Thus, we hypothesized that a drug which induces degradation of mtEGFR independent of
the ATP binding domain will result in selective activity. Our objective is to evaluate the therapeutic potential of
DGD1202 in a panel of lung cancer cells lines, xenografts, and PDXs derived from lung cancer patients
containing mtEGFR who have undergone treatment with a TKI.
Specific Aims: We propose to evaluate the specificity and potency of DGD1202 against TKI-resistant lung
cancer cells and xenografts. Aim 1 is to determine the in vitro efficacy of DGD1202 against a panel of EGFR
driven, including osimertinib-resistant, cancer cell lines relative to normal cells. Aim 2 is to conduct in vivo
pharmacokinetic (PK) and pharmacodynamic (PD) analyses to assess drug exposure and determine the effect
on the target. Aim 3 is to determine the overall therapeutic efficacy and long-term safety of DGD1202 in vivo.
We hypothesize that treatment with DGD1202 will induce EGFR degradation preferentially in tumor cells driven
by mtEGFR and that EGFR degradation will correlate with the overall response.
Study Design: We will screen DGD1202 alongside osimertinib in a series of lung cancer lines. The resulting
response will be then correlated with effect on EGFR degradation. We also propose to determine in vivo PK
and PD studies both with a single and with fractionated dosing to determine the optimum bioavailability. Using
the optimized dose and schedule, we will assess effects on EGFR protein against a panel mtEGFR-driven and
osimertinib resistant lung cancer xenograft and PDX models. The long-term safety will be assessed in immune
competent mice. Standard statistical models will be used to compare the response to treatment and how it
correlates with effects on EGFR.
Impact: We anticipate that our approach will open a new way to target EGFR and, more broadly, to develop
therapeutics to selectively target mutated proteins to degradation. The knowledge gained from in vivo tumor
models will provide a rationale for the use of this class of molecules in future clinical studies.
背景:肺癌通常由突变型表皮生长因子受体(mtEGFR)驱动。而
EGFR酪氨酸激酶活性抑制剂(TKI)已显示出有效性,所有患者在9-13个月内
产生耐药性,包括对第三代TKI -奥希替尼的耐药性。这些患者没有任何批准的
因此,迫切需要开发一种新的药物,其功能独立于治疗选择。
激酶功能DGD 1202,一种新型口服生物可利用小分子,可抑制EGFR
二聚化诱导EGFR降解并选择性杀死TKI抗性NSCLC肿瘤。
目的:我们和其他人已经表明,突变型EGFR蛋白的降解对EGFR的表达有深远的影响。
癌细胞存活率因此,我们假设一种诱导mtEGFR降解的药物,
ATP结合结构域将导致选择性活性。我们的目标是评估
一组肺癌细胞系、异种移植物和源自肺癌患者的PDX中的DGD 1202
接受过TKI治疗的患者。
具体目的:我们建议评价DGD 1202对TKI耐药肺的特异性和效力。
癌细胞和异种移植物。目的1是确定DGD 1202对一组EGFR的体外疗效
相对于正常细胞,包括奥西替尼耐药的癌细胞系。目的2是在体内进行
药代动力学(PK)和药效学(PD)分析,以评估药物暴露并确定效应
目标上。目的3是确定DGD 1202在体内的总体疗效和长期安全性。
我们假设用DGD 1202治疗将在肿瘤细胞中优先诱导EGFR降解,
通过mtEGFR,EGFR降解将与总体反应相关。
研究设计:我们将在一系列肺癌细胞系中筛选DGD 1202和奥希替尼。所得
然后将反应与对EGFR降解的影响相关联。我们还建议测定体内PK
以及单次和分次给药的PD研究,以确定最佳生物利用度。使用
优化的剂量和时间表,我们将评估对EGFR蛋白的影响,
奥希替尼抗性肺癌异种移植物和PDX模型。将在免疫组化中评估长期安全性。
有能力的老鼠将使用标准统计模型比较治疗反应以及
与对EGFR的影响相关。
影响:我们预计,我们的方法将开辟一种新的方式来靶向EGFR,更广泛地说,
选择性靶向突变蛋白质以降解的治疗剂。从体内肿瘤获得的知识
模型将为在未来的临床研究中使用这类分子提供理论基础。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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THEODORE S LAWRENCE其他文献
THEODORE S LAWRENCE的其他文献
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{{ truncateString('THEODORE S LAWRENCE', 18)}}的其他基金
Molecularly Targeted Radiosensitization of Locally Advanced Cancers
局部晚期癌症的分子靶向放射增敏
- 批准号:
10554470 - 财政年份:2023
- 资助金额:
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Targeting Stromal Influences on BCKA Addiction in PDAC Tumors
靶向基质对 PDAC 肿瘤 BCKA 成瘾的影响
- 批准号:
10453984 - 财政年份:2022
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$ 33.35万 - 项目类别:
Targeting Stromal Influences on BCKA Addiction in PDAC Tumors
靶向基质对 PDAC 肿瘤 BCKA 成瘾的影响
- 批准号:
10581670 - 财政年份:2022
- 资助金额:
$ 33.35万 - 项目类别:
Development of a first-in-class mEGFR dimerization inhibitor
开发一流的 mEGFR 二聚化抑制剂
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10591476 - 财政年份:2020
- 资助金额:
$ 33.35万 - 项目类别:
Development of a first-in-class mEGFR dimerization inhibitor
开发一流的 mEGFR 二聚化抑制剂
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$ 33.35万 - 项目类别:
Development of a first-in-class mEGFR dimerization inhibitor
开发一流的 mEGFR 二聚化抑制剂
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- 批准号:
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