THE ROLE OF STAT3 SIGNALING IN CHILDHOOD SARCOMAS
STAT3 信号传导在儿童肉瘤中的作用
基本信息
- 批准号:8516641
- 负责人:
- 金额:$ 31.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-05 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntibodiesAntitumor ResponseApoptosisBiological AvailabilityBiological MarkersCanis familiarisCell LineCell ProliferationCell SurvivalCellsCellular AssayChildChildhoodClinicalCollaborationsDataDiseaseDominant-Negative MutationDoseDrug resistanceEvaluationEwings sarcomaExhibitsGenesGoalsGrowth FactorI-kappa B ProteinsImmuneIn VitroInstructionInsulin-Like Growth Factor IInsulin-Like Growth Factor IIInterleukin-6InvestigationMediatingMetastatic toMethodsMicroRNAsModelingMolecularMusNF-kappa BNeoplasm MetastasisOralOutcomePET/CT scanPTPRC genePathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPrimary NeoplasmRegimenRhabdomyosarcomaRoleSTAT3 geneSamplingSerumSignal PathwaySignal TransductionSmall Interfering RNASolubilitySomatomedinsSpecificityStat3 proteinTherapeutic InterventionToxic effectTranslatingTreatment EfficacyTumor Cell LineTumor SuppressionWorkXenograft ModelXenograft procedureanalogangiogenesisautocrinecell growthcytokineeffective therapyimmune functionimprovedin vivoin vivo Modelinhibitor/antagonistmembermouse modelneoplastic cellnovelosteosarcomaparacrineprogramssarcomasmall moleculetherapeutic targettumortumor growthtumorigenesis
项目摘要
The constitutive activation of Signal Transducer and Activator of Transcription 3 (STATS) is frequently
detected in cell lines and patient samples of the three most frequently occurring childhood sarcomas,
rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. Constitutive STAT3 signaling participates in
tumorigenesis by stimulating cell proliferation, mediating immune evasion, promoting angiogenesis, and
conferring drug resistance. The central hypothesis of this project is that constitutive STATS signaling is
required and critical for survival and tumorigenesis in these childhood sarcomas and as such, inhibition of
STATS activity represents a viable approach for therapeutic intervention. This hypothesis is supported by our
data demonstrating that a dominant negative form of STATS, STATS small interfering RNA (siRNA), and the
small molecule allosteric STATS inhibitor LLL12 can inhibit proliferation and induce apoptosis of childhood
sarcoma cell lines. We have developed an analog of LLL12, LY5, that exhibits several advantages including
enhanced specificity for STATS, increased potency as evidenced by biologic activity at lower drug
concentrations, greater solubility and predicted oral bioavailability, and a simpler method for synthesis. The
objectives of this proposal are to build on these initial findings and identify the signals responsible for STATS
activation in childhood sarcomas, and evaluate the efficacy of LY5 using a combination of studies with tumor
cell lines, mouse models of childhood sarcomas (xenografts, orthotopic tumors and metastatic tumors), and
a canine model of spontaneous osteosarcoma. Our long-term objective is to use combined therapy of a
STATS-selective inhibitor with iGF-1R (Project 3) and NF-kappa B (Project 1) inhibitors and ultimately
improve outcome for childhood sarcomas. The following specific aims will be studied: 1) Investigate the
molecular mechanisms responsible for STATS activation in sarcoma cells; 2) Evaluate the inhibitory efficacy
of the novel STATS-selective small molecular inhibitor, LY5 on sarcoma cells in vitro and mouse sarcoma
models in vivo; and 3) Determine the biologic activity and clinical toxicities of STATS inhibition in
spontaneous canine osteosarcoma.
RELEVANCE (See instructions):
Constitutive activation of STATS is frequently detected in childhood sarcomas and blocking STATS activity
inhibits tumor cell growth in vitro and suppresses tumor growth in mouse xenograft models. Constitutive
STATS signaling is crucial to the survival of sarcoma cells and may serve as a therapeutic target. Therefore,
the evaluation of targeted STATS therapy is relevant and significant to the childhood sarcoma treatments.
信号转导子和转录激活子3(STATs)的组成性激活通常是
在三种最常见的儿童肉瘤的细胞系和患者样本中检测到,
横纹肌肉瘤、骨肉瘤和尤文氏肉瘤。组成型STAT 3信号传导参与
通过刺激细胞增殖,介导免疫逃避,促进血管生成,
从而产生抗药性。该项目的中心假设是组成性STATS信号传导是
这些儿童肉瘤的生存和肿瘤发生所需的和关键的,因此,抑制
STATS活性代表了治疗干预的可行方法。这一假设得到了我们的支持。
数据表明,显性阴性形式的STATS,STATS小干扰RNA(siRNA),
小分子变构STATS抑制剂LLL 12可抑制儿童乳腺癌细胞增殖并诱导其凋亡
肉瘤细胞系。我们已经开发了LLL 12的类似物LY 5,其表现出几个优点,包括
增强对STATS的特异性,增加效力,如在较低药物浓度下的生物活性所证明的
本发明提供了更高浓度、更大的溶解度和预测的口服生物利用度以及更简单的合成方法。的
本建议的目标是在这些初步研究结果的基础上,确定负责STATS的信号
激活儿童肉瘤,并评估LY 5的疗效使用的研究与肿瘤
细胞系、儿童肉瘤的小鼠模型(异种移植物、原位肿瘤和转移性肿瘤),以及
自发性骨肉瘤的犬模型。我们的长期目标是使用联合治疗,
STAT选择性抑制剂与iGF-1 R(项目3)和NF-κ B(项目1)抑制剂,
改善儿童肉瘤预后。研究的具体目标如下:(1)调查
负责肉瘤细胞中STATS激活的分子机制; 2)评估抑制功效
新型STAT选择性小分子抑制剂LY 5对体外肉瘤细胞和小鼠肉瘤的作用
体内模型;和3)确定STATS抑制的生物活性和临床毒性,
自发性犬骨肉瘤
相关性(参见说明):
在儿童肉瘤中经常检测到STATS的组成性激活,
在体外抑制肿瘤细胞生长和在小鼠异种移植模型中抑制肿瘤生长。本构
STATS信号传导对肉瘤细胞的存活至关重要,并可作为治疗靶点。因此,我们认为,
STATS靶向治疗的评价对儿童肉瘤的治疗具有重要意义。
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 }}
Jiayuh Lin其他文献
Jiayuh Lin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('Jiayuh Lin', 18)}}的其他基金
Co-Targeting IL-6 and CDK4/6 Pathways as a Novel Approach of Preventive Therapy for Triple-Negative Breast Cancer
共同靶向 IL-6 和 CDK4/6 通路作为三阴性乳腺癌预防性治疗的新方法
- 批准号:
10365726 - 财政年份:2022
- 资助金额:
$ 31.73万 - 项目类别:
Co-Targeting IL-6 and CDK4/6 Pathways as a Novel Approach of Preventive Therapy for Triple-Negative Breast Cancer
共同靶向 IL-6 和 CDK4/6 通路作为三阴性乳腺癌预防性治疗的新方法
- 批准号:
10655282 - 财政年份:2022
- 资助金额:
$ 31.73万 - 项目类别:
A novel STAT3-selective inhibitor for medulloblastoma therapy
一种用于髓母细胞瘤治疗的新型 STAT3 选择性抑制剂
- 批准号:
9291724 - 财政年份:2016
- 资助金额:
$ 31.73万 - 项目类别:
Repositioning Bazedoxifene as a novel IL-6/GP130 inhibitor for sarcoma therapy
将巴多昔芬重新定位为用于肉瘤治疗的新型 IL-6/GP130 抑制剂
- 批准号:
9291661 - 财政年份:2016
- 资助金额:
$ 31.73万 - 项目类别:
Repositioning Bazedoxifene as a novel IL-6/GP130 inhibitor for sarcoma therapy
将巴多昔芬重新定位为用于肉瘤治疗的新型 IL-6/GP130 抑制剂
- 批准号:
8996140 - 财政年份:2015
- 资助金额:
$ 31.73万 - 项目类别:
A new curcumin analogue with potent suppressive activity in pancreatic cancer
一种新的姜黄素类似物,对胰腺癌具有有效的抑制活性
- 批准号:
7874486 - 财政年份:2009
- 资助金额:
$ 31.73万 - 项目类别:
A new curcumin analogue with potent suppressive activity in pancreatic cancer
一种新的姜黄素类似物,对胰腺癌具有有效的抑制活性
- 批准号:
7740282 - 财政年份:2009
- 资助金额:
$ 31.73万 - 项目类别:
Evaluation of a novel AKT inhibitor in ovarian cancer
新型 AKT 抑制剂治疗卵巢癌的评价
- 批准号:
6703347 - 财政年份:2004
- 资助金额:
$ 31.73万 - 项目类别:
Evaluation of a novel AKT inhibitor in ovarian cancer
新型 AKT 抑制剂治疗卵巢癌的评价
- 批准号:
7017651 - 财政年份:2004
- 资助金额:
$ 31.73万 - 项目类别:
Regulation of Stat3 by p53 in cancer Cells
癌细胞中 p53 对 Stat3 的调节
- 批准号:
6779707 - 财政年份:2002
- 资助金额:
$ 31.73万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 31.73万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 31.73万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 31.73万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 31.73万 - 项目类别:
Research Grant
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别:
Grant for R&D
PLA2G2D Antibodies for Cancer Immunotherapy
用于癌症免疫治疗的 PLA2G2D 抗体
- 批准号:
10699504 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别:
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别:
Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface
新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体
- 批准号:
10782567 - 财政年份:2023
- 资助金额:
$ 31.73万 - 项目类别: