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.

信号转导子和转录激活子 3 (STATS) 的组成型激活经常发生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 STAT3 信号参与通过刺激细胞增殖、介导免疫逃避、促进血管生成和赋予耐药性。该项目的中心假设是本构 STATS 信号传导是对于这些儿童肉瘤的生存和肿瘤发生来说是必需且至关重要的，因此，抑制 STATS 活动代表了一种可行的治疗干预方法。这个假设得到了我们的支持数据表明 STATS 的显性失活形式、STATS 小干扰 RNA (siRNA) 和小分子变构STATS抑制剂LLL12可抑制细胞增殖并诱导细胞凋亡肉瘤细胞系。我们开发了 LLL12 的类似物 LY5，它具有多种优势，包括 STATS 的特异性增强，效力增加（通过较低药物的生物活性证明）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。这该提案的目标是建立在这些初步发现的基础上，并确定导致 STATS 的信号儿童肉瘤中的激活，并结合肿瘤研究评估 LY5 的功效细胞系、儿童肉瘤小鼠模型（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。我们的长期目标是采用综合疗法 STATS 选择性抑制剂与 iGF-1R（项目 3）和 NF-kappa B（项目 1）抑制剂，最终改善儿童肉瘤的治疗效果。将研究以下具体目标： 1）调查肉瘤细胞中 STATS 激活的分子机制； 2) 评价抑制效果新型STATS选择性小分子抑制剂LY5对体外肉瘤细胞和小鼠肉瘤的影响体内模型； 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（参见说明）：在儿童肉瘤中经常检测到 STATS 的组成性激活并阻断 STATS 活性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。本构型 STATS 信号传导对于肉瘤细胞的存活至关重要，并且可以作为治疗靶点。所以， STATS靶向治疗的评价对于儿童肉瘤的治疗具有相关性和意义。