Probing INTS11 as a novel target in neuroblastoma
探索 INTS11 作为神经母细胞瘤的新靶点
基本信息
- 批准号:10577214
- 负责人:
- 金额:$ 7.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-07 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:1p36AnabolismBiologicalCell LineCell ProliferationCellsChildChromosomesCodeComplexCoupledDataDependenceDiagnosisDown-RegulationEndoribonucleasesFDA approvedGene ExpressionGenesGenetic TranscriptionGenomicsInfantLaboratoriesMYCN geneMalignant NeoplasmsMeasuresMolecularMutationNeuroblastomaNormal CellOutputPharmaceutical PreparationsPropertyProteinsRNARNA Polymerase IIRNA ProcessingRNA SplicingReagentRecyclingReporterResearchResearch Project GrantsRoleRunningSpliceosomesSurvival RateSystemTestingToxic effectTumor Suppressor GenesTumor Suppressor ProteinsTumorigenicityUnited Statesdesigndruggable targethigh riskhigh throughput screeninginhibitorknock-downmRNA Precursormemberneuroblastoma cellnew therapeutic targetnovelpatient prognosispharmacologicsmall hairpin RNAsmall moleculesmall molecule inhibitortumorvirtual
项目摘要
PROJECT SUMMARY
Nearly a thousand children are diagnosed each year with Neuroblastoma (NBL) in the United States, and
this cancer is, by far, the most prevalent type in infants. Sadly, high-risk NBL, which comprises ~70% of
all NBL cases, has a five-year survival rate of <50%. High-risk NBL is characterized by having
amplification of the MYCN gene and deletion of the 1p36 (D1p36) region of chromosome one, which
houses multiple tumor suppressors. But these signatures are difficult to exploit as pharmacologic
inhibition of MYCN has proven elusive, and re-activating tumor suppressor gene expression after
genomic loss is virtually impossible. Consistent with MYCN’s established role in increasing global
transcription, high-risk NBLs with amplified MYCN expression are uniquely dependent on the cellular
transcription and RNA processing apparatus. Among this machinery vital to MYCN function is the
Integrator Complex, which is responsible for UsnRNA biosynthesis essential for co-transcriptional splicing
and promoting RNA polymerase II (RNAPII) turnover and plasticity. Integrator is a 14-membered complex
associated with RNAPII and is fundamental in regulating transcriptional output. My laboratory has been
investigating the molecular mechanism of Integrator for over ten years(19-34), and we have found that
Integrator subunit 11 (INTS11) is the critical enzymatic component of the complex. INTS11 utilizes its
RNA endonuclease activity to cleave the 3'-end of spliceosomal UsnRNA and is thus required for pre-
mRNA splicing. Moreover, we recently found that INTS11 is also necessary to cleave nascent protein-
coding RNA to promote RNAPII recycling. Both functions are critical to support high transcription
observed when MYCN is overproduced. Beyond being required in MYCN-amplified tumors, the most
attractive feature nominating Integrator as a potential druggable target in NBL is that the INTS11 gene is
located within 1p36 and is frequently deleted in NBLs. In support of this observation, data from DEPMAP
reveals that NBL cell lines are highly sensitive to partial depletion of INTS11, indicating a unique and
robust dependency on this gene. Altogether, these observations support a hypothesis that INTS11
represents a novel and unexplored target in NBL (Fig. 1), and our Specific Aims below are designed to
test this directly. Specific Aim 1. Determine the sensitivity of MYCN-amplified and D1p36 NBL cell lines
to INTS11 downregulation. Specific Aim 2. Test candidate inhibitors of INTS11 for differential toxicity in
high-risk NBL cell lines.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ERIC J WAGNER其他文献
ERIC J WAGNER的其他文献
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{{ truncateString('ERIC J WAGNER', 18)}}的其他基金
Alternative Cleavage and Polyadenylation Events as Biomarkers
作为生物标志物的替代切割和聚腺苷酸化事件
- 批准号:
8600659 - 财政年份:2013
- 资助金额:
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Alternative Cleavage and Polyadenylation Events as Biomarkers
作为生物标志物的替代切割和聚腺苷酸化事件
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8428364 - 财政年份:2013
- 资助金额:
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A HTS Assay for Inhibitors of Proximal Cleavage and Polyadenylation
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8624669 - 财政年份:2012
- 资助金额:
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A HTS Assay for Inhibitors of Proximal Cleavage and Polyadenylation
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- 批准号:
8445320 - 财政年份:2012
- 资助金额:
$ 7.7万 - 项目类别:
A HTS Assay for Inhibitors of Proximal Cleavage and Polyadenylation
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8273217 - 财政年份:2012
- 资助金额:
$ 7.7万 - 项目类别:
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7905148 - 财政年份:2007
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$ 7.7万 - 项目类别:
Characterizing Novel Components Involved in 3' End Processing of Histone pre-mRNA
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7639777 - 财政年份:2007
- 资助金额:
$ 7.7万 - 项目类别:
Characterizing Novel Components Involved in 3' End Processing of Histone pre-mRNA
表征组蛋白前体 mRNA 3 末端加工中涉及的新成分
- 批准号:
7385301 - 财政年份:2007
- 资助金额:
$ 7.7万 - 项目类别:
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- 资助金额:
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