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.
信号换能器和转录激活因子3 (STATS)的本构激活是频繁的
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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