Targeting S1PR1/JAK2/STAT3 Signaling Axis in EMDR

EMDR 中针对 S1PR1/JAK2/STAT3 信号轴

• 批准号: 8555323
• 负责人: Hua E Yu
• 金额: $ 19.25万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555323
• 关键词: Address; Apoptotic; Biological Assay; Biological Models; Blood; Bone Marrow; Bone Marrow Cells; Bone Marrow Neoplasms; Cells; Clinic; Clinical; Clinical Trials; Coculture Techniques; DNA Methylation; Drug resistance; Environment; G-Protein-Coupled Receptors; Genes; Genetic; Human; In Vitro; Interleukin-6; JAK2 gene; Knock-out; Knockout Mice; Lead; Learning; Link; Lung; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; Neuroblastoma; Oncogenic; Patients; Pharmaceutical Preparations; Phospholipids; Production; Protein Tyrosine Kinase; Reagent; Receptor Signaling; Resistance; Resources; Role; STAT3 gene; Sampling; Signal Transduction; Solid; Solid Neoplasm; Stromal Cells; System; Technology; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Tumor Suppressor Proteins; Work; Xenograft procedure; bone; cancer therapy; cancer type; cell type; chemotherapy; effective therapy; feeding; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; neuroblastoma cell; novel; prevent; research clinical testing; research study; resistance factors; small molecule; transcription factor; tumor; tumor growth

This project is aimed at identifying effective targets to address a major problem facing cancer treatment: bone marrow environment-mediated drug resistance (EMDR). One potential key target that may prevent/reduce EMDR is STATS, in part because it is persistenfiy activated in both tumor cells and in the tumor microenvironment, and because it is a transcription factor that regulates expression of numerous tumorpromoting and drug resistance factors. Many of these factors are also STATS activators, thereby forming a feed-foHA/ard loop linking tumor cells with the tumor microenvironment. lL-6, produced by bone marrow stromal cells has been shown to activate STATS in neuroblastoma cells (collaborative work with Project 1), leading to tumor growth and EMDR, Our preliminary studies show that ablafing STATS in bone marrow-derived cells prevents formation of lung niches that harbor metastatic tumor cells. However, due to a lack of intrinsic enzymatic activity, there are no clinical reagents to specifically target some of the key oncogenic transcription factors such as STATS. Our recent studies demonstrate that STATS upregulates expression of S1PR1, a key G protein-coupled receptor for the phospholipid metabolite, SIP. SI PRI, in turn, activates STATS through tyrosine kinase JAK2, which is also critical for IL-6 receptor signaling. Elevafing SI PRI expression in either tumor cells or bone marrow-derived myeloid cells leads to production of numerous factors that promote STATS-dependent niche formation to provide sanctuary for tumor cells. Furthermore, recent studies implicate SI PRI in mediating drug resistance of both solid and blood-borne cancers, including ALL. Importantly, both SI PRI and JAK2 inhibitors have recently entered clinical trials. We therefore propose to test the hypothesis that targeting S1PR1/JAK2/STAT3 signaling in bone marrow stromal cells will effectively inhibit EMDR for both neuroblastoma and ALL. We will test our hypothesis in co-cultures of neuroblastoma and ALL tumor cells with mouse and patient bone marrow stromal cells, and in syngeneic transgenic mouse and xenograft neuroblastoma/ALL models. We will also adapt a novel in vivo ectopic bone-forming system to reproduce the tumor/bone marrow niche (both mouse and human). With the availability of transgenic mice and SiRNA technologies allowing S1PR1, JAK2, or STAT3 knockout/knockdown in specific types of bone marrow cells as well as the availability of small molecule drugs currently under clinical tesfing, our proposed studies may lead to paradigm-shifting novel therapies to overcome EMDR in neuroblastoma, ALL, and other types of cancer.

该项目旨在确定有效的目标来解决癌症治疗面临的一个主要问题：骨 骨髓环境介导的耐药性（EMDR）。一个可能预防/减少的潜在关键目标 EMDR 是 STATS，部分原因是它在肿瘤细胞和肿瘤中持续激活 微环境，并且因为它是调节许多促肿瘤细胞表达的转录因子 和耐药因素。其中许多因素也是 STATS 激活剂，从而形成 feed-foHA/ard 环将肿瘤细胞与肿瘤微环境连接起来。 lL-6，由骨髓基质产生 细胞已被证明可以激活神经母细胞瘤细胞中的 STATS（与项目 1 合作），从而导致 肿瘤生长和 EMDR，我们的初步研究表明，骨髓来源细胞中的消融 STATS 防止形成含有转移性肿瘤细胞的肺生态位。但由于缺乏内在的 酶活性，没有临床试剂可以专门针对一些关键的致癌转录 统计等因素。我们最近的研究表明 STATS 上调 S1PR1 的表达，这是一个关键的 磷脂代谢物 SIP 的 G 蛋白偶联受体。 SI PRI 反过来通过以下方式激活 STATS： 酪氨酸激酶 JAK2，对于 IL-6 受体信号转导也至关重要。提升 SI PRI 表达 肿瘤细胞或骨髓来源的骨髓细胞会产生多种促进细胞生长的因子 STATS 依赖性生态位形成为肿瘤细胞提供庇护所。此外，最近的研究表明 SI PRI 介导实体癌和血源性癌症（包括 ALL）的耐药性。重要的是，两者 SI PRI 和 JAK2 抑制剂最近已进入临床试验。因此我们建议检验假设 靶向骨髓基质细胞中的S1PR1/JAK2/STAT3信号传导将有效抑制EMDR 对于神经母细胞瘤和 ALL。我们将在神经母细胞瘤和 ALL 的共培养中检验我们的假设 小鼠和患者骨髓基质细胞中的肿瘤细胞，以及同基因转基因小鼠和 异种移植神经母细胞瘤/ALL模型。我们还将采用一种新颖的体内异位骨形成系统 复制肿瘤/骨髓生态位（小鼠和人类）。随着转基因小鼠的出现和 SiRNA 技术允许在特定类型的骨髓中敲除/敲低 S1PR1、JAK2 或 STAT3 细胞以及目前正在进行临床测试的小分子药物的可用性，我们提出的研究 可能会带来范式转变的新疗法，以克服神经母细胞瘤、ALL 和其他类型的 EMDR 癌症。