Targeting STAT3 to enhance anti-tumor immunity

靶向STAT3增强抗肿瘤免疫力

基本信息

项目摘要

ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is a common and lethal cancer, where 5-year survival rates have lingered at roughly 40-60% for several decades. Our long-term objective is to develop effective, well-tolerated agents and strategies to improve the outcomes of patients with HNSCC. The recent approval of the PD-1 checkpoint inhibitors nivolumab and pembrolizumab for HNSCC suggests that targeting central mediators of immunosuppression in the tumor microenvironment will lead to significant improvements in treatment. Inhibition of the oncogenic transcription factor STAT3 represents a promising new strategy for relieving immunosuppression. STAT3 is hyperactivated in HNSCC, where it contributes to tumor growth, production of immunosuppressive cytokines, and poor prognosis. STAT3 is also hyperactivated in tumor infiltrating immune cells. Conditional deletion of stat3 in murine hematopoietic cells has revealed potent immunosuppressive roles for STAT3 in multiple immune cell populations. Thus, selective targeting of STAT3 may yield a three-fold anti-tumor benefit: a) direct inhibition of tumor cell growth, b) inhibition of cell- autonomous immunosuppression in immune cells, and c) relief of immunosuppressive cross-talk between tumor and immune cells. However, currently available STAT3 inhibitors either lack potency and specificity, or cannot be delivered systemically. To overcome this obstacle we designed a 15-bp duplex oligonucleotide, the STAT3 decoy, which resembles a STAT3 response element, binds selectively to activated STAT3, induces HNSCC apoptosis, and suppresses the growth of xenograft tumors. A Phase 0 trial involving intratumoral injection of this STAT3 decoy demonstrated downmodulation of STAT3 target genes in HNSCC tumors. A cyclic version of STAT3 decoy exhibits improved stability and nuclease resistance, and inhibits the growth of xenograft tumors following systemic delivery to immunodeficient mice. The impact of the cyclic STAT3 decoy on the immune system has never been studied, limiting the design of further clinical trials with this promising anti-cancer agent. We will utilize immunocompetent murine models of HNSCC to rigorously evaluate the effects on the immune system of cyclic STAT3 decoy, alone and in combination with PD-1 inhibition. In addition, we will evaluate safety, immune effects and potential efficacy, of the cyclic STAT3 decoy in a unique and valuable animal model of naturally occurring HNSCC in pet cats. Our studies will test the hypothesis that targeted inhibition of STAT3 via systemic administration of cyclic STAT3 decoy will enhance anti-tumor immunity in immunocompetent mouse models of HNSCC and augment the effects of PD-1 checkpoint inhibition, while exhibiting minimal toxicity in pet cats with naturally occurring HNSCC. Results from our studies will determine the potential for relieving immunosuppression in HNSCC using cyclic STAT3 decoy, while laying the foundation for clinical advancement of this highly innovative and selective STAT3 inhibitor.
摘要

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jennifer Rubin Grandis其他文献

Retinoic acid normalizes the increased gene transcription rate of TGF–α and EGFR in head and neck cancer cell lines
维甲酸可使头颈癌细胞系中 TGF–α 和 EGFR 基因转录速率增加恢复正常
  • DOI:
    10.1038/nm0296-237
  • 发表时间:
    1996-02-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Jennifer Rubin Grandis;Qing Zeng;David J. Tweardy
  • 通讯作者:
    David J. Tweardy
Phospholipase C-γ1 in tumor progression
  • DOI:
    10.1023/a:1024088922957
  • 发表时间:
    2003-07-01
  • 期刊:
  • 影响因子:
    3.200
  • 作者:
    Alan Wells;Jennifer Rubin Grandis
  • 通讯作者:
    Jennifer Rubin Grandis

Jennifer Rubin Grandis的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Jennifer Rubin Grandis', 18)}}的其他基金

Targeting STAT3 to enhance anti-tumor immunity
靶向STAT3增强抗肿瘤免疫力
  • 批准号:
    10621927
  • 财政年份:
    2019
  • 资助金额:
    $ 63万
  • 项目类别:
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy
整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗
  • 批准号:
    9982266
  • 财政年份:
    2018
  • 资助金额:
    $ 63万
  • 项目类别:
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy
整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗
  • 批准号:
    10664975
  • 财政年份:
    2018
  • 资助金额:
    $ 63万
  • 项目类别:
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy
整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗
  • 批准号:
    9764300
  • 财政年份:
    2018
  • 资助金额:
    $ 63万
  • 项目类别:
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy
整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗
  • 批准号:
    10224700
  • 财政年份:
    2018
  • 资助金额:
    $ 63万
  • 项目类别:
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy
整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗
  • 批准号:
    10456330
  • 财政年份:
    2018
  • 资助金额:
    $ 63万
  • 项目类别:
Clinical and Translational Science Institute
临床与转化科学研究所
  • 批准号:
    9341569
  • 财政年份:
    2016
  • 资助金额:
    $ 63万
  • 项目类别:
Clinical and Translational Science Institute
临床与转化科学研究所
  • 批准号:
    9317561
  • 财政年份:
    2016
  • 资助金额:
    $ 63万
  • 项目类别:
PI3K Pathway Mutations in Head and Neck Cancer
头颈癌中的 PI3K 通路突变
  • 批准号:
    10398070
  • 财政年份:
    2014
  • 资助金额:
    $ 63万
  • 项目类别:
GPCR Signaling in SCCHN: Integration with EGFR
SCCHN 中的 GPCR 信号转导:与 EGFR 整合
  • 批准号:
    8606299
  • 财政年份:
    2014
  • 资助金额:
    $ 63万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了