RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies

RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应

基本信息

项目摘要

Project Summary Ovarian carcinoma is the fifth deadliest cancer among women in the United States. In spite of advances in surgical resection and platinum-taxane combination therapy over the past several decades, cure rates remain relatively low (~30%) and a majority of women diagnosed with advanced ovarian cancer will die with drug-resistant disease within 5 years. The long-term goal of this project, “RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Anti-Cancer Therapies”, is to identify specific RNA-binding proteins that, together with their upstream protein kinase regulators, control the resistance and sensitivity of high-grade serous ovarian cancers to these clinically used first line anti-cancer therapies. The project involves: (1) a detailed computational analysis that queries pre-existing publically available RNA expression data using RNA-BP recognition motifs to identify specific RNA binding proteins whose mRNA targets are up- or down- regulated in ovarian cancer patients with chemo-sensitive versus chemo-resistant tumors; and (2) an independent CRISPR-interference and CRISPR-activation genome-wide screen for RNA-BPs whose manipulation alters the resistance and sensitivity of ovarian cancer cells to platinum and taxane agents in vitro, and in vivo using cell line xenografts and human PDX ovarian cancer mouse models. The RNA-BPs identify by these two complimentary approaches, together with a collection of RNA-BPs that we have already identified in previous experiments and preliminary data, are then directly validated for their effects on drug resistance in these model systems, and the identity of their bound RNAs and their effects on gene expression determined using CLIP technologies and RNA-Seq. In selected cases the importance of specific phosphorylation sites on RNA-BP function is examined to further elucidate the molecular basis for anti-cancer drug resistance through pathway-specific regulation of RNA-BP action. The project builds on a broad foundation of expertise and related work from all of the co-Investigators laboratories. Expected outcomes from the studies include the identification of specific RNA-BPs and upstream regulatory kinase pathways whose targeting can prevent or reverse the resistance of ovarian cancers to current clinically used front-lime therapeutics; the elucidation of new molecular circuits that control gene expression in cancers after chemotherapy treatment; and the creation of a suite of web-based tools available to the entire scientific community that can be used to query any set of differentially expressed genes for RNA-BP-based regulation, particularly in a form that is optimized for analysis of new and existing cancer patient RNA expression datasets.
项目总结

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.
  • DOI:
    10.3389/fimmu.2020.607891
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Suarez-Lopez L;Kong YW;Sriram G;Patterson JC;Rosenberg S;Morandell S;Haigis KM;Yaffe MB
  • 通讯作者:
    Yaffe MB
Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.
功能基因组学揭示了胃癌治疗中药物协同作用的脱靶依赖性。
  • DOI:
    10.1101/2023.10.07.561351
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Leylek,Ozen;Honeywell,MeganE;Lee,MichaelJ;Hemann,MichaelT;Ozcan,Gulnihal
  • 通讯作者:
    Ozcan,Gulnihal
Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
  • DOI:
    10.1038/s41467-021-26407-4
  • 发表时间:
    2021-10-28
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Bent EH;Millán-Barea LR;Zhuang I;Goulet DR;Fröse J;Hemann MT
  • 通讯作者:
    Hemann MT
Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.
早期免疫变化支持 CDH1 驱动的遗传性弥漫性胃癌中印戒细胞休眠。
  • DOI:
    10.1158/1541-7786.mcr-23-0122
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Green,BenjaminL;Gamble,LaurenA;Diggs,LaurenceP;Nousome,Darryl;Patterson,JesseC;Joughin,BrianA;Gasmi,Billel;Lux,StephanieC;Samaranayake,SarahG;Miettinen,Markku;Quezado,Martha;Hernandez,JonathanM;Yaffe,MichaelB;Davis,Jere
  • 通讯作者:
    Davis,Jere
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CHRISTOPHER B BURGE其他文献

CHRISTOPHER B BURGE的其他文献

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{{ truncateString('CHRISTOPHER B BURGE', 18)}}的其他基金

Regulation and Function of Alternative mRNA Isoform Expression in Mammals
哺乳动物中替代 mRNA 同工型表达的调节和功能
  • 批准号:
    10540339
  • 财政年份:
    2021
  • 资助金额:
    $ 52.58万
  • 项目类别:
Regulation and Function of Alternative mRNA Isoform Expression in Mammals
哺乳动物中替代 mRNA 同工型表达的调节和功能
  • 批准号:
    10323056
  • 财政年份:
    2021
  • 资助金额:
    $ 52.58万
  • 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
  • 批准号:
    10054974
  • 财政年份:
    2018
  • 资助金额:
    $ 52.58万
  • 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
  • 批准号:
    10305607
  • 财政年份:
    2018
  • 资助金额:
    $ 52.58万
  • 项目类别:
Bioinformatics
生物信息学
  • 批准号:
    9149750
  • 财政年份:
    2015
  • 资助金额:
    $ 52.58万
  • 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
  • 批准号:
    8684871
  • 财政年份:
    2014
  • 资助金额:
    $ 52.58万
  • 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
  • 批准号:
    8852097
  • 财政年份:
    2014
  • 资助金额:
    $ 52.58万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8310598
  • 财政年份:
    2012
  • 资助金额:
    $ 52.58万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8628858
  • 财政年份:
    2012
  • 资助金额:
    $ 52.58万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8463015
  • 财政年份:
    2012
  • 资助金额:
    $ 52.58万
  • 项目类别:

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