Molecular mechanisms of BRAF inhibitor induced UPR and autophagy

BRAF抑制剂诱导UPR和自噬的分子机制

基本信息

  • 批准号:
    9768184
  • 负责人:
  • 金额:
    $ 35.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The dramatic responses observed in patients with BRAF mutant melanoma treated with BRAF inhibitors reflect a major therapeutic breakthrough in melanoma. However, there are multiple resistance mechanisms that arise in patient tumors that limit the effectiveness of BRAF inhibitors. We have found that autophagy is activated in patient tumors and cell lines treated with BRAF inhibitors, and this therapy-associated autophagy protects melanoma cells and contributes to regrowth of tumors. Our previous work establishes that BRAF inhibitors activate autophagy by activating an early ER stress response which in turn gives rise to cytoprotective autophagy. In this proposal, the PI will work closely with the co-investigator, combining their respective expertise in autophagy, melanoma biology and treatment, and the ER stress response to elucidate the mechanistic underpinnings of the mutant BRAF-ER stress-autophagy signaling. Our hypothesis is that certain components of the ER stress pathway are critical for BRAF inhibitor-induced autophagy, and therefore could serve as novel targets for combinations regimens. Our strategy will be to first determine the molecular mechanism that links mutant BRAF with the ER stress response and autophagy (aim 1); then elucidate the biological effects of targeting specific components of the ER stress response or autophagy in BRAFi-induced cell death in 2D and 3D melanoma culture (aim 2); and to characterize the role of BRAFi-induced ER stress and autophagy in vivo using genetic and pharmacological inhibition of ER stress or autophagy in combination with BRAF inhibition (aim 3). The focus of these studies is on the development of a sophisticated understanding of the mechanistic links between these three pathways. The knowledge gained from these studies will increase our understanding about the fundamental biology of BRAF mutant melanoma, the interaction between mutant BRAF and the ER stress response, the role of cytoplasmic GRP78 in the response to targeted therapy, and the mechanisms by which the ER stress response regulates autophagy. Besides these fundamental advances, this project has translational potential because it will investigate these pathways in an enrolling trial of BRAF and autophagy inhibition in BRAF mutant melanoma patients, and it will identify potential new combinations that may be even more effective for future clinical trials.
 描述(由适用提供):用BRAF抑制剂治疗的BRAF突变瘤患者观察到的显着反应反映了黑色素瘤的主要治疗突破。但是,在患者肿瘤中存在多种抗性机制,这些机制限制了BRAF抑制剂的有效性。我们发现,在用BRAF抑制剂治疗的患者肿瘤和细胞系中激活自噬,并且该治疗相关的自噬可保护黑色素瘤细胞并有助于肿瘤的改革。我们以前的工作确定BRAF抑制剂通过激活早期的ER应力反应来激活自噬,从而导致细胞保护自噬。在此提案中,PI将与共同投资者紧密合作,结合其在自噬,黑色素瘤生物学和治疗方面的专业知识,以及ER应力反应以阐明突变体Braf-BRAF-BRAF-ER应激 - 嗜硫醇信号的机械基础。我们的假设是,ER应力途径的某些成分对于BRAF抑制剂引起的自噬至关重要,因此可以作为组合方案的新靶标。我们的策略将首先确定将突变体BRAF与ER应力反应和自噬联系起来的分子机制(AIM 1);然后阐明靶向Brafi诱导的2D和3D黑色素瘤培养物中BRAFI诱导的细胞死亡的ER应激反应或自噬的生物学效应(AIM 2);并表征Brafi诱导的ER应力和自噬在体内的作用,使用遗传和药物抑制ER应激或自噬与BRAF抑制结合使用(AIM 3)。这些研究的重点是对这三个途径之间机械联系的复杂理解的发展。从这些研究中获得的知识将增加我们对BRAF突变黑色素瘤的基本生物学的理解,突变体BRAF与ER应激反应之间的相互作用,细胞质GRP78在对靶向治疗反应中的作用以及ER应力反应调节自噬的机制。除了这些基本进展外,该项目还将潜力转化,因为它将在BRAF突变黑色素瘤患者的BRAF和自噬抑制试验中调查这些途径,并且它将确定潜在的新组合,这些新组合可能对未来的临床试验更有效。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting the unfolded protein response in cancer.
  • DOI:
    10.1016/j.phrs.2017.04.003
  • 发表时间:
    2017-06
  • 期刊:
  • 影响因子:
    9.3
  • 作者:
    Ojha R;Amaravadi RK
  • 通讯作者:
    Amaravadi RK
共 1 条
  • 1
前往

RAVI K AMARAVADI的其他基金

Resistance mechanisms to autophagy-modulating therapies
自噬调节疗法的耐药机制
  • 批准号:
    10345115
    10345115
  • 财政年份:
    2022
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Resistance mechanisms to autophagy-modulating therapies
自噬调节疗法的耐药机制
  • 批准号:
    10565868
    10565868
  • 财政年份:
    2022
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Targeting autophagy to enhance immune checkpoint inhibition
靶向自噬增强免疫检查点抑制
  • 批准号:
    10480852
    10480852
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
SPORE in Skin Cancer
皮肤癌中的孢子
  • 批准号:
    10480828
    10480828
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Targeting autophagy to enhance immune checkpoint inhibition
靶向自噬增强免疫检查点抑制
  • 批准号:
    10268745
    10268745
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
SPORE in Skin Cancer
皮肤癌中的孢子
  • 批准号:
    10268740
    10268740
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Molecular mechanisms of BRAF inhibitor induced UPR and autophagy
BRAF抑制剂诱导UPR和自噬的分子机制
  • 批准号:
    8945350
    8945350
  • 财政年份:
    2015
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Molecular mechanisms of BRAF inhibitor induced UPR and autophagy
BRAF抑制剂诱导UPR和自噬的分子机制
  • 批准号:
    9131669
    9131669
  • 财政年份:
    2015
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
HLTF gene silencing: a novel determinant of sensitivity to autophagy inhibition
HLTF 基因沉默:自噬抑制敏感性的新决定因素
  • 批准号:
    8664818
    8664818
  • 财政年份:
    2013
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
HLTF gene silencing: a novel determinant of sensitivity to autophagy inhibition
HLTF 基因沉默:自噬抑制敏感性的新决定因素
  • 批准号:
    8843267
    8843267
  • 财政年份:
    2013
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:

相似国自然基金

晚期妊娠维持和抑制早产中cAMP信号活化PR的作用机制研究
  • 批准号:
    81300507
  • 批准年份:
    2013
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Mechanisms of viral RNA maturation by co-opting cellular exonucleases
通过选择细胞核酸外切酶使病毒 RNA 成熟的机制
  • 批准号:
    10814079
    10814079
  • 财政年份:
    2023
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
Mechanisms of viral RNA maturation by co-opting cellular exonucleases
通过选择细胞核酸外切酶使病毒 RNA 成熟的机制
  • 批准号:
    10463469
    10463469
  • 财政年份:
    2022
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement
FMRP 介导的人脑发育和治疗进展调节
  • 批准号:
    10443845
    10443845
  • 财政年份:
    2020
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement
FMRP 介导的人脑发育和治疗进展调节
  • 批准号:
    10678925
    10678925
  • 财政年份:
    2020
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别:
FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement
FMRP 介导的人脑发育和治疗进展调节
  • 批准号:
    10271305
    10271305
  • 财政年份:
    2020
  • 资助金额:
    $ 35.5万
    $ 35.5万
  • 项目类别: