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
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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Jian Yu其他文献
Jian Yu的其他文献
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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
- 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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- 资助金额:
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PUMA 和 p21 协调调节肠道干细胞的存活和更新
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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:
$ 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:
7935368 - 财政年份:2009
- 资助金额:
$ 45.98万 - 项目类别:
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