A novel STAT3-selective inhibitor for medulloblastoma therapy

 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。持续的STAT3激活经常在人成神经管细胞瘤细胞系和儿童中最常见的恶性脑肿瘤成神经管细胞瘤的原发肿瘤中检测到。该项目的中心假设是：STAT3磷酸化在四个髓母细胞瘤组的癌组织中表达，并且使用LY5与顺铂和放射疗法组合靶向持续的STAT3信号传导是髓母细胞瘤治疗的有效方法。我们最近的数据表明STAT3磷酸化在髓母细胞瘤细胞系和原发性肿瘤样品中表达，这一假设得到了支持。LY5抑制人髓母细胞瘤细胞系的细胞活力并诱导细胞凋亡，但在正常人细胞和无肿瘤的正常免疫活性小鼠中几乎没有毒性。此外，我们观察到LY5与顺铂或放射联合对髓母细胞瘤细胞具有更强的抑制作用。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。本提案的目的是建立在这些初步发现的基础上，以进一步了解负责成神经管细胞瘤中STAT3激活的上游信号传导，不同亚组中的STAT3激活，并评价成神经管细胞瘤小鼠模型中联合治疗的生物活性。我们的长期目标是将STAT3选择性抑制剂如LY5作为成神经管细胞瘤治疗的STAT3靶向药物进行临床评价。我们将通过以下具体目标来验证中心假设：（1）表征四个髓母细胞瘤亚群中STAT3的磷酸化，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功效。

 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.