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)
抽象的
该项目的重点是开发由激活的肺肿瘤驱动的有效疗法
ERK 信号通路,特别是由 KRAS 或 BRAF 突变驱动的信号通路
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
突变的 KRAS 或二聚体依赖性非 V600 BRAF 突变或融合;部分是因为适应性
对 RAF 或 MEK 抑制剂的耐药性,这是通过 ERK 依赖性反馈的缓解来介导的;部分是因为
BRAF V600 肿瘤产生获得性耐药;并且由于 MEK 抑制剂的毒性。在最后
资助期间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;制定了具体机制
抑制每一类突变体的方法;鉴定出 RAF 单体的新型等价抑制剂
用于治疗 1 类和 2 类 RAF 突变体的二聚体;鉴定出具有增强能力的 MEK 抑制剂
抑制突变 RAS 驱动的 MEK;并表征并确定了直接的作用机制
KRAS G12C(肺癌中最常见的突变 RAS 等位基因)的抑制剂。该提案的目标是
使用这些抑制剂来了解每种癌蛋白在肺癌中的作用并探究它们的作用
临床前开发。目标 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,并为 1 类和 2 类突变体开发治疗方案。目标2
涉及 3 类 BRAF 突变体(肺癌中最常见的一类)的研究,并开发了一种新的方法
抑制其活性的机制。目标 3 涉及 KRAS G12C 抑制剂的临床前开发
及其用于研究突变 RAS 在肺癌中的功能作用及其抑制的后果。
抑制任何突变体驱动的 ERK 信号传导有望缓解 ERK 依赖性反馈抑制
信号传递并有助于适应性抵抗。我们将与 RP4 合作开展这方面的研究
抑制 RAS/RAF/MEK 信号传导的每种方法的过程,尝试确定所需的途径
肿瘤细胞的存活,并在此基础上发展联合治疗。
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 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:
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:
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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