A novel STAT3-selective inhibitor for medulloblastoma therapy

一种用于髓母细胞瘤治疗的新型 STAT3 选择性抑制剂

• 批准号: 9291724
• 负责人: Jiayuh Lin
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291724
• 关键词: Address; Adverse effects; Antineoplastic Agents; Apoptosis; Bioavailable; Biological; Biological Availability; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Proliferation; Cell Survival; Cells; Cellular Assay; Child; Childhood Medulloblastomas; Cisplatin; Clinical; Clinical Trials; Data; Drug Kinetics; Drug Targeting; Drug resistance; Exhibits; Goals; Growth; Health; Human; Immune; Immunocompetent; Individual; Induction of Apoptosis; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Normal Cell; Oncogenic; Oral; Outcome; PTPRC gene; Pathway interactions; Patients; Penetration; Phosphorylation; Plasma; Primary Neoplasm; Progressive Disease; Radiation; Radiation therapy; Role; SHH gene; Sampling; Signal Pathway; Signal Transduction; Slide; Small Interfering RNA; Stat3 protein; Subgroup; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Tissue Microarray; Tissues; Toxic effect; Tumor Volume; Xenograft procedure; angiogenesis; base; cancer therapy; circulating microRNA; cytokine; improved; in vivo Model; inhibitor/antagonist; irradiation; medulloblastoma; medulloblastoma cell line; migration; mouse model; neoplastic cell; novel; radiation resistance; research clinical testing; targeted treatment; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): Constitutive STAT3 signaling participates in tumorigenesis by stimulating cell proliferation, mediating immune evasion, promoting angiogenesis, conferring drug and radiation resistance, and tumorigenesis. The persistent STAT3 activation is frequently detected in human medulloblastoma cell lines and primary tumors of the most frequently occurring malignant brain tumor, medulloblastoma, in children. The central hypotheses of this project are: STAT3 phosphorylation is expressed in cancer tissues in four medulloblastoma groups and targeting persistent STAT3 signaling using LY5 in combination with cisplatin and radiation therapy is an effective approach for medulloblastoma therapy. The hypotheses are supported by our recent data demonstrating that STAT3 phosphorylation is expressed in medulloblastoma cell lines and primary tumor samples. LY5 inhibited cell viability and induced apoptosis of human medulloblastoma cell lines but has little toxicity in normal human cells and tumor-free normal immunocompetent mice. In addition, we observed that combination of LY5 with cisplatin or irradiation exhibited stronger inhibitory effect in medulloblastoma cells. Furthermore, our preliminary the pharmacokinetic data showed that LY5 has high oral bioavailability and good blood brain barrier penetration. The objectives of this proposal are to build on these initial findings to further understand the upstream signaling responsible for STAT3 activation in medulloblastoma, STAT3 activation in different subgroups, and to evaluate the biologic activity of combinational treatments in medulloblastoma mouse models. Our long-term objective is to move a STAT3- selective inhibitor such as LY5 into clinical evaluation in patients as a STAT3-targeting drug for medulloblastoma therapy. We will test the central hypotheses through the following specific aims: (1) Characterize STAT3 phosphorylation in four subgroups of medulloblastoma and investigate the mechanisms responsible for STAT3 activation. (2) Characterize the biologic effects of the novel STAT3 inhibitor LY5 on medulloblastoma cells. (3) Evaluate the inhibitory efficacy of LY5 in mouse medulloblastoma models in vivo.

 描述（由申请人提供）：组成型STAT3信号传导通过刺激细胞增殖、介导免疫逃避、促进血管生成、赋予药物和辐射抗性以及肿瘤发生来参与肿瘤发生。在人髓母细胞瘤细胞系和儿童中最常见的恶性脑肿瘤（髓母细胞瘤）的原发性肿瘤中经常检测到持续的 STAT3 激活。该项目的中心假设是：STAT3磷酸化在四个髓母细胞瘤组的癌症组织中表达，并且使用LY5联合顺铂和放射治疗来靶向持续的STAT3信号传导是髓母细胞瘤治疗的有效方法。我们最近的数据证明了 STAT3 磷酸化在髓母细胞瘤细胞系和原发性肿瘤样本中表达，这些假设得到了支持。 LY5 抑制人髓母细胞瘤细胞系的细胞活力并诱导细胞凋亡，但对正常人细胞和无肿瘤的正常免疫活性小鼠几乎没有毒性。此外，我们观察到LY5与顺铂联合或放射治疗对髓母细胞瘤细胞表现出更强的抑制作用。此外，我们初步的药代动力学数据表明LY5具有较高的口服生物利用度和良好的血脑屏障渗透性。该提案的目的是在这些初步发现的基础上，进一步了解负责髓母细胞瘤中 STAT3 激活、不同亚组中 STAT3 激活的上游信号传导，并评估髓母细胞瘤小鼠模型中联合治疗的生物学活性。我们的长期目标是将 STAT3 选择性抑制剂（例如 LY5）作为髓母细胞瘤治疗的 STAT3 靶向药物进入临床评估。我们将通过以下具体目标检验中心假设：（1）表征髓母细胞瘤四个亚组中的 STAT3 磷酸化，并研究 STAT3 激活的机制。 (2) 表征新型STAT3抑制剂LY5对髓母细胞瘤细胞的生物学效应。 (3)评价LY5在小鼠髓母细胞瘤模型中的体内抑制效果。