Project 2: Targeting the ERK Pathway in KRAS- and BRAF-Driven Lung Cancers
项目 2:针对 KRAS 和 BRAF 驱动的肺癌中的 ERK 通路
基本信息
- 批准号:10246297
- 负责人:
- 金额:$ 29.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesBRAF geneBiochemicalBiologicalBiological ProcessBiological Response Modifier TherapyBiologyCell SurvivalClinicalClinical TrialsCollaborationsCombined Modality TherapyDataDevelopmentDrug resistanceEffectivenessExposure toFGFR1 geneFeedbackFundingGenesGoalsGrowthHumanIn VitroKRAS2 geneLungLung AdenocarcinomaLung NeoplasmsMEK inhibitionMEKsMalignant neoplasm of lungMediatingMediator of activation proteinMethodsMinorityModelingMutationNon-Small-Cell Lung CarcinomaOncoproteinsPathway interactionsPharmaceutical PreparationsPharmacologyPhenotypePhosphotransferasesProcessProto-OncogenesRAS inhibitionRas/RafReceptor Protein-Tyrosine KinasesRegimenResistanceResistance developmentRoleSignal PathwaySignal TransductionTestingTherapeuticTherapeutic EffectToxic effectTreatment ProtocolsWorkantitumor effectbaseclinical effectdimereffective therapyfallsin vivoinhibitor/antagonistlung Carcinomamonomermutantneoplastic cellnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpreclinical developmentpreventresistance mechanismtargeted treatmenttherapeutically effectivetumortumor growth
项目摘要
Lung P01 Competing (1/25/17)
Project 2 (Rosen, PI)
ABSTRACT
This project is focused on the development of effective therapies for lung tumors driven by activation of the
ERK signaling pathway, particularly those in which the pathway is driven by mutations in the KRAS or BRAF
proto-oncogenes. These tumors are particularly difficult to treat, in part because there are no direct inhibitors of
mutant KRAS or of dimer-dependent non-V600 BRAF mutations or fusions; in part because of adaptive
resistance to RAF or MEK inhibitors, which is mediated by relief of ERK dependent feedback; in part because
BRAF V600 tumors develop acquired resistance; and because of the toxicity of MEK inhibitors. In the last
funding period we made material progress in overcoming these obstacles. We discovered that BRAF mutants
fall into three functional classes based on their mechanism of activation; developed specific mechanism-based
methods of inhibition of each class of mutant; identified novel equipotent inhibitors of RAF monomers and
dimers for the treatment of Class 1 and 2 RAF mutants; identified MEK inhibitors with an enhanced ability to
inhibit MEK driven by mutant RAS; and characterized and determined the mechanism of action of direct
inhibitors of KRAS G12C, the most common mutant RAS allele in lung cancer. The goal of the proposal is to
use these inhibitors to understand the role of each of these oncoproteins in lung cancer and pursue their
preclinical development. Aim 1 concerns the use of the RAF dimer/monomer inhibitor to understand the role of
Class 2 dimer-dependent BRAF mutants and to develop treatment regimens for Class 1 and 2 mutants. Aim 2
concerns the study of Class 3 BRAF mutants, the most common class in lung cancer, and exploits a novel
mechanism for inhibiting their activity. Aim 3 concerns the preclinical development of the KRAS G12C inhibitor
and its use to study the functional role of mutant RAS in lung cancer and the consequences of its inhibition.
Inhibiting ERK signaling driven by any of the mutants is expected to relieve ERK-dependent feedback inhibition
of signaling and contribute to adaptive resistance. In collaboration with RP4, we will undertake the study of this
process for each of these methods of inhibiting RAS/RAF/MEK signaling, attempt to identify pathways required
for tumor cell survival, and develop combination therapy on this basis.
肺P01竞争(1/25/17)
项目2(罗森,PI)
摘要
该项目的重点是开发有效的治疗肺肿瘤的方法,
ERK信号传导途径,特别是其中该途径由KRAS或BRAF中的突变驱动的那些
原癌基因这些肿瘤特别难以治疗,部分原因是没有直接的抑制剂。
突变型KRAS或二聚体依赖性非V600 BRAF突变或融合;部分原因是适应性
对RAF或MEK抑制剂的抗性,这是由ERK依赖性反馈的缓解介导的;部分原因是
BRAF V600肿瘤产生获得性耐药性;并且由于MEK抑制剂的毒性。在过去
我们在克服这些障碍方面取得了实质性进展。我们发现BRAF突变体
根据其激活机制分为三个功能类别;基于特定机制开发
抑制每类突变体的方法;鉴定RAF单体的新的等效抑制剂,
用于治疗1类和2类RAF突变体的二聚体;鉴定了MEK抑制剂,
抑制由突变RAS驱动的MEK;并表征和确定了直接
KRAS G12 C抑制剂,肺癌中最常见的突变RAS等位基因。该提案的目标是
使用这些抑制剂来了解这些癌蛋白中的每一种在肺癌中的作用,
临床前开发。目的1涉及使用RAF二聚体/单体抑制剂来了解
2类二聚体依赖性BRAF突变体,并开发1类和2类突变体的治疗方案。目的2
涉及3类BRAF突变体的研究,这是肺癌中最常见的一类,并利用了一种新的
抑制其活性的机制。目的3涉及KRAS G12 C抑制剂的临床前开发
及其用于研究突变型RAS在肺癌中的功能作用及其抑制的后果。
预期抑制由任何突变体驱动的ERK信号传导将减轻ERK依赖性反馈抑制
并有助于适应性抵抗。我们将与RP 4合作,研究这一问题。
这些抑制RAS/RAF/MEK信号传导的方法中的每一种的过程,试图鉴定所需的途径,
促进肿瘤细胞存活,并在此基础上开发联合治疗。
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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NEAL ROSEN的其他文献
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{{ truncateString('NEAL ROSEN', 18)}}的其他基金
Studies on oncoprotein-induced feedback: Basic and therapeutic implications
癌蛋白诱导反馈的研究:基本和治疗意义
- 批准号:
10247722 - 财政年份:2016
- 资助金额:
$ 29.04万 - 项目类别:
Studies on oncoprotein-induced feedback: Basic and therapeutic implications
癌蛋白诱导反馈的研究:基本和治疗意义
- 批准号:
9766084 - 财政年份:2016
- 资助金额:
$ 29.04万 - 项目类别:
Studies on oncoprotein-induced feedback: Basic and therapeutic implications
癌蛋白诱导反馈的研究:基本和治疗意义
- 批准号:
9186828 - 财政年份:2016
- 资助金额:
$ 29.04万 - 项目类别:
Clinical Development of Next-Generation Antiandrogens and the Impact of PTEN Status
下一代抗雄激素的临床开发和 PTEN 状态的影响
- 批准号:
8730087 - 财政年份:2014
- 资助金额:
$ 29.04万 - 项目类别:
Developing therapeutic strategies for ERK-dependent tumors
开发 ERK 依赖性肿瘤的治疗策略
- 批准号:
8906506 - 财政年份:2013
- 资助金额:
$ 29.04万 - 项目类别:
Developing therapeutic strategies for ERK-dependent tumors
开发 ERK 依赖性肿瘤的治疗策略
- 批准号:
8741950 - 财政年份:2013
- 资助金额:
$ 29.04万 - 项目类别:
Developing therapeutic strategies for ERK-dependent tumors
开发 ERK 依赖性肿瘤的治疗策略
- 批准号:
8632319 - 财政年份:2013
- 资助金额:
$ 29.04万 - 项目类别:
Development of Methodologies for the In Vivo Imaging og the Effects of Novel Inhi
体内成像方法的开发和新型 Inhi 的效果
- 批准号:
7729470 - 财政年份:2008
- 资助金额:
$ 29.04万 - 项目类别:
Development of Mechanism-Based Strategies for the Treatment of Advanced Breast Ca
开发基于机制的晚期乳腺癌治疗策略
- 批准号:
7438486 - 财政年份:2008
- 资助金额:
$ 29.04万 - 项目类别:
HSP90 AS A TARGET FOR MECHANISM-BASED THERAPY FOR CASTRATION-RESISTANT PROSTATE C
HSP90 作为去势抵抗性前列腺癌基于机制治疗的靶点
- 批准号:
7147036 - 财政年份:2005
- 资助金额:
$ 29.04万 - 项目类别:
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