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.

信号传感器的本构激活和转录3的激活因子（统计）经常是在三个最常发生的儿童肉瘤中检测到的细胞系和患者样本，横纹肌肉瘤，骨肉瘤和尤因的肉瘤。构型STAT3信令参与肿瘤发生通过刺激细胞增殖，介导免疫逃避，促进血管生成和赋予耐药性。该项目的中心假设是构型统计信号传导是这些儿童肉瘤中的生存和肿瘤发生所需和至关重要 Stats活动代表了治疗干预的可行方法。这个假设得到了我们的支持数据表明，统计数据的主要负面形式，统计数据较小的干扰RNA（siRNA）和小分子变构抑制剂LLL12可以抑制增殖并诱导儿童凋亡肉瘤细胞系。我们已经开发了一个Lll12，Ly5的类似物，该类似物具有多种优势统计数据的特异性提高，效力提高了，在较低的药物下生物学活性证明了效力浓度，更大的溶解度和预测的口服生物利用度以及一种更简单的合成方法。这该提案的目标是建立在这些初始发现的基础上，并确定负责统计的信号儿童肉瘤的激活，并使用肿瘤研究组合评估LY5的功效细胞系，儿童肉瘤的小鼠模型（异种移植物，原位肿瘤和转移性肿瘤）和自发骨肉瘤的犬类模型。我们的长期目标是使用合并的疗法具有IGF-1R（项目3）和NF-KAPPA B（项目1）抑制剂的统计选择抑制剂，最终改善儿童肉瘤的结果。将研究以下特定目标：1）调查负责肉瘤细胞中数据激活的分子机制； 2）评估抑制功效新型统计选择性的小分子抑制剂，体外和小鼠肉瘤的肉瘤细胞上的LY5 体内模型； 3）确定在抑制数据的生物学活性和临床毒性自发犬骨肉瘤。相关性（请参阅说明）：在儿童期肉瘤和阻止统计活动中，经常检测到统计数据的本构激活抑制体外肿瘤细胞生长，并抑制小鼠异种移植模型中的肿瘤生长。本构统计信号传导对于肉瘤细胞的存活至关重要，可以作为治疗靶标。所以，对靶向数据治疗的评估与儿童肉瘤疗法有关，并且与儿童肉瘤疗法有关。