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.
信号转导和转录激活因子3(STATS)的结构性激活是经常发生的
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。结构型STAT3信号参与
通过刺激细胞增殖,介导免疫逃避,促进血管生成,以及
产生抗药性。该项目的中心假设是构成STATS信号是
对这些儿童肉瘤的生存和肿瘤形成是必需的和关键的,因此,抑制
STATS活动代表了一种可行的治疗干预方法。这一假设得到了我们的
数据表明,STATS的一种主要阴性形式,STATS小干扰RNA(SiRNA),以及
小分子变构STATS抑制剂LLL12抑制儿童期细胞增殖和诱导细胞凋亡
肉瘤细胞系。我们已经开发了LLL12的模拟物LY5,它显示了几个优点,包括
STATS的特异性增强,效力增强,这是通过较低药物的生物活性来证明的
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。这个
这项提案的目标是在这些初步发现的基础上,确定导致STATS的信号
儿童肉瘤中的激活,并结合肿瘤研究评估LY5的疗效
细胞系,儿童肉瘤的小鼠模型(异种移植、原位肿瘤和转移肿瘤),以及
犬自发性骨肉瘤模型。我们的长期目标是使用综合疗法治疗
使用IGF-1R(项目3)和NF-kappa B(项目1)抑制剂的STATS选择性抑制剂,并最终
改善儿童肉瘤的预后。将研究以下具体目标:1)调查
STATS在肉瘤细胞中激活的分子机制;2)评价其抑制效果
新型STATS选择性小分子抑制剂LY5对肉瘤细胞和小鼠肉瘤的体外抑制作用
体内模型;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(请参阅说明):
在儿童肉瘤中经常检测到STATS的结构性激活并阻断STATS的活性
体外抑制肿瘤细胞生长,抑制小鼠异种移植模型肿瘤生长。构成要素
STATS信号对肉瘤细胞的生存至关重要,可能成为治疗的靶点。因此,
对靶向STATS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)
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Jiayuh Lin其他文献
Jiayuh Lin的其他文献
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