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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：
Jiayuh Lin
金额：
$ 31.73万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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：
https://reporter.nih.gov/project-details/8516641
关键词：
Animal Model Antibodies Antitumor Response Apoptosis Biological Availability Biological Markers Canis familiaris Cell Line Cell Proliferation Cell Survival Cells Cellular Assay Child Childhood Clinical Collaborations Data Disease Dominant-Negative Mutation Dose Drug resistance Evaluation Ewings sarcoma Exhibits Genes Goals Growth Factor I-kappa B Proteins Immune In Vitro Instruction Insulin-Like Growth Factor I Insulin-Like Growth Factor II Interleukin-6 Investigation Mediating Metastatic to Methods MicroRNAs Modeling Molecular Mus NF-kappa B Neoplasm Metastasis Oral Outcome PET/CT scan PTPRC gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Primary Neoplasm Regimen Rhabdomyosarcoma Role STAT3 gene Sampling Serum Signal Pathway Signal Transduction Small Interfering RNA Solubility Somatomedins Specificity Stat3 protein Therapeutic Intervention Toxic effect Translating Treatment Efficacy Tumor Cell Line Tumor Suppression Work Xenograft Model Xenograft procedure analog angiogenesis autocrine cell growth cytokine effective therapy immune function improved in vivo in vivo Model inhibitor/antagonist member mouse model neoplastic cell novel osteosarcoma paracrine programs sarcoma small molecule therapeutic target tumor tumor growth tumorigenesis

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