Translation addiction and targeting in colon cancer
结肠癌的翻译成瘾和靶向治疗
基本信息
- 批准号:10317055
- 负责人:
- 金额:$ 45.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:APC mutationAcuteAffectBRAF geneCancer BiologyCancer Cell GrowthCancer EtiologyCell DeathCell LineCell ProliferationCell SurvivalCell modelCessation of lifeClinicalColon CarcinomaColorectal CancerComplexDataDependenceDevelopmentEukaryotic Initiation Factor-4FEvolutionFRAP1 geneFeedbackGenetic TranscriptionGenetic TranslationGlutamineHumanHyperactivityIndividualIntestinal PolyposisKRAS2 geneKnock-inLeadMalignant NeoplasmsMediatingMetabolicMetabolic stressMetabolismModelingMusMutationNormal tissue morphologyOncogenicPI3K/AKTPathway interactionsPharmacologyPhosphorylationPhosphotransferasesProteinsPublicationsRNA Cap-Binding ProteinsRas/RafResistanceRoleSamplingSignal TransductionSpecificityStressSystems BiologyTNFRSF10B geneTestingToxic effectTranscriptTranslatingTranslationsWNT Signaling PathwayWorkXenograft procedureaddictionarmbiological adaptation to stressc-myc Genescancer cellcancer initiationcancer therapycolon cancer treatmenteffective therapyendoplasmic reticulum stressimprovedin vivoinhibitorinnovationmouse modelmulticatalytic endopeptidase complexmutantnovelnovel drug combinationpatient derived xenograft modelpotential biomarkerprogramspublic health relevancesuccesstargeted treatmenttooltranslational approachtumor progressiontumorigenesis
项目摘要
Summary
Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its
development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However,
targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate
eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209,
or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal
tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer
and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports
a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer
proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F
induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the
project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent
metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this
hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development.
SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in
colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation
defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches
to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better
understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to
target this addiction for therapy. These findings will likely have important implications in treating other cancers
with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.
总结
结直肠癌(CRC)是美国和世界范围内癌症死亡的主要原因,并且其
发育由Wnt、RAS/RAF/ERK和PI 3 K/AKT/mTOR信号传导的突变激活驱动。然而,在这方面,
以CRC中的单个驱动程序为目标的成功有限。Wnt、mTOR和ERK信号传导会聚以解除调节
eIF 4F和导致翻译关键致癌靶点,包括c-Myc。有趣的是,磷酸化eIF 4 E(S209,
或p-eIF 4 E)对于开发或全球翻译是不必要的,但对于转化和优化是必需的。
在某些模型中的肿瘤发生。p-eIF 4 E在人类肿瘤中升高的原因及意义
而致癌基因的翻译在很大程度上仍是未知的。我们的新的初步数据和最近的出版物支持
p-eIF 4 E在人类和小鼠结肠癌发展中的关键作用,以及在调节结肠癌中的关键作用
增殖通过ATF 4介导的代谢和应激适应。eIF 4 E/4F的药理学靶向
在培养物和体内诱导内质网应激和CRC细胞死亡。的中心假设
项目是磷酸化eIF 4 E通过ATF 4依赖性驱动结肠癌的发生和进展
代谢和压力重编程,并作为一个可操作的和药物的脆弱性。我们将测试这个
三个具体目标的假设。SA 1.定义eIF 4 E磷酸化在结肠癌发展中的作用。
SA 2.阐明结肠癌中p-eIF 4 E依赖性肿瘤发生的机制。SA 3.目标eIF 4F/4 E,
结肠癌治疗拟议的工作将开发和采用创新工具,包括磷酸化
缺陷性eIF 4 E癌细胞和小鼠、临床样品以及高度机械和全面的方法
以确定p-eIF 4 E在结肠癌生物学和治疗中的作用。如果成功,我们的工作将提供更好的
了解保护性应激和代谢适应中的致癌基因翻译,以及
针对这种成瘾进行治疗这些发现可能对治疗其他癌症有重要意义
Wnt和RAS/RAF过度活跃,目前尚无有效治疗方法。
项目成果
期刊论文数量(2)
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 Myc-driven stress addiction in colorectal cancer.
- DOI:10.1016/j.drup.2023.100963
- 发表时间:2023-07
- 期刊:
- 影响因子:24.3
- 作者:Saeed, Haris;Leibowitz, Brian J.;Zhang, Lin;Yu, Jian
- 通讯作者:Yu, Jian
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{{ truncateString('Jian Yu', 18)}}的其他基金
STING-dependent Intestinal Regeneration upon Radiation Injury
放射损伤时 STING 依赖性肠道再生
- 批准号:
10386172 - 财政年份:2022
- 资助金额:
$ 45.98万 - 项目类别:
Targeting defective necroptosis in colorectal cancer
靶向结直肠癌中的缺陷性坏死性凋亡
- 批准号:
10307591 - 财政年份:2019
- 资助金额:
$ 45.98万 - 项目类别:
Targeting defective necroptosis in colorectal cancer
靶向结直肠癌中的缺陷性坏死性凋亡
- 批准号:
10054976 - 财政年份:2019
- 资助金额:
$ 45.98万 - 项目类别:
Targeting defective necroptosis in colorectal cancer
靶向结直肠癌中的缺陷性坏死性凋亡
- 批准号:
9914466 - 财政年份:2019
- 资助金额:
$ 45.98万 - 项目类别:
Translation addiction and targeting in colon cancer
结肠癌的翻译成瘾和靶向治疗
- 批准号:
10063486 - 财政年份:2018
- 资助金额:
$ 45.98万 - 项目类别:
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8534110 - 财政年份:2009
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Intestinal Stem Cell Survival and Renewal Coordinately Regulated by PUMA and p21
PUMA 和 p21 协调调节肠道干细胞的存活和更新
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PUMA 和 p21 协调调节肠道干细胞的存活和更新
- 批准号:
8134688 - 财政年份:2009
- 资助金额:
$ 45.98万 - 项目类别:
Intestinal Stem Cell Survival and Renewal Coordinately Regulated by PUMA and p21
PUMA 和 p21 协调调节肠道干细胞的存活和更新
- 批准号:
8328970 - 财政年份:2009
- 资助金额:
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Intestinal Stem Cell Survival and Renewal Coordinately Regulated by PUMA and p21
PUMA 和 p21 协调调节肠道干细胞的存活和更新
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7935368 - 财政年份:2009
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