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

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.
Lung P01竞速(1/25/17)

项目成果

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会议论文数量(0)
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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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BRAF gene mutation causes hallmarks of cancer associated with tumor microenvironment
BRAF基因突变导致与肿瘤微环境相关的癌症特征
  • 批准号:
    18K14582
  • 财政年份:
    2018
  • 资助金额:
    $ 29.04万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Significance of BRAF gene mutation on tumor microenvironment
BRAF基因突变对肿瘤微环境的意义
  • 批准号:
    16K20968
  • 财政年份:
    2016
  • 资助金额:
    $ 29.04万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Evaluation of radiation effect based on point mutation of BRAF gene
基于BRAF基因点突变的放射效果评价
  • 批准号:
    15K12202
  • 财政年份:
    2015
  • 资助金额:
    $ 29.04万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Analysis of tumor clonality using SNPs surrounding BRAF gene and its association with clinicopathological features
BRAF基因周围SNP分析肿瘤克隆性及其与临床病理特征的关系
  • 批准号:
    19790651
  • 财政年份:
    2007
  • 资助金额:
    $ 29.04万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
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