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

基本信息

  • 批准号:
    10247722
  • 负责人:
  • 金额:
    $ 107.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT We have established that oncoproteins which function as dysregulated components of mitogenic signaling pathways cause marked feedback inhibition of physiologic signaling. Much of our recent work has focused on understanding the implications of this phenomenon. Insensitivity to feedback inhibition of receptor activation of wild type RAS is a common property of oncoproteins that activated ERK signaling that is required for them to elevate ERK output. Second, elevated pathway output includes elevated feedback inhibition of physiologic signaling pathways. This is a major determinant of the so- called oncoprotein dependence of transformed cells. Third, feedback-dependent oncoprotein pathway dependence reduces the robustness of the cell and creates a selection for mutations that activate feedback-Inhibited pathways and restores robustness. This accounts for some of the secondary driver mutations identified in tumors. Finally, inhibitors of oncoprotein-activated signaling have significant antitumor activity, but also relieve feedback inhibition of physiologic mitogenic signaling pathways and cause their reactivation. This attenuates their antitumor activity and creates a logic for inhibiting key reactivated pathways in tumors exposed to inhibitors of oncoproteins. This strategy has had some early clinical success and has become a paradigm for the development of rational combination therapies. Despite these insights, we still know only few of the details of oncoprotein-induced feedback and its relief by targeted inhibitors. We do know that these details vary as a function of tumor lineage and which pathway component is mutationally activated. Moreover, the effects of relieving feedback also vary depending on which node of the pathway is pharmacologically inhibited. We now plan to comprehensively study feedback and its relief by nodal inhibitors, focusing on a few tumors and using both methodologies biased by previous knowledge of normal signaling and unbiased shRNA screens. We utilize selective inhibitors of PI3K, AKT, mTOR, RAF, MEK, ERK, and a novel allele-specific inhibitor of RAS and study both short- and long-term adaptation, to determine whether some of the effects of the latter are due to epigenetic regulation. The goal is to develop new effective combination therapies based on these data and on in vivo studies to determine dose schedules that optimize induction of cell death.
项目摘要/摘要

项目成果

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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:
    9766084
  • 财政年份:
    2016
  • 资助金额:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 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:
    $ 107.76万
  • 项目类别:
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
  • 批准号:
    10246297
  • 财政年份:
    2007
  • 资助金额:
    $ 107.76万
  • 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:
    $ 107.76万
  • 项目类别:

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