A novel STAT3-selective inhibitor for medulloblastoma therapy

 描述(申请人提供)：结构性STAT3信号通过刺激细胞增殖、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而参与肿瘤的发生。在人类髓母细胞瘤细胞系和儿童最常见的恶性脑肿瘤-髓母细胞瘤的原发肿瘤中，经常检测到持续的STAT3激活。该项目的中心假设是：STAT3磷酸化在四组髓母细胞瘤的癌组织中表达，使用LY5联合顺铂和放射治疗靶向持续的STAT3信号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肿瘤样本中表达，这一假设得到了支持。LY5对人髓母细胞瘤细胞系有抑制作用，对人髓母细胞瘤细胞系有诱导凋亡作用，但对正常人细胞和无肿瘤免疫功能的正常小鼠无明显毒性。此外，我们还观察到LY5联合顺铂或放疗对髓母细胞瘤细胞有较强的抑制作用。此外，我们的初步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通透性。该方案的目的是在这些初步发现的基础上，进一步了解在髓母细胞瘤中STAT3激活的上游信号，以及不同亚组中STAT3的激活，并评估联合治疗在髓母细胞瘤小鼠模型中的生物学活性。我们的长期目标是将STAT3选择性抑制剂，如LY5，作为髓母细胞瘤治疗的STAT3靶向药物，应用于患者的临床评估。我们将通过以下具体目标来检验中心假说：(1)表征髓母细胞瘤四个亚组中STAT3的磷酸化，并研究STAT3激活的机制。(2)研究新型STAT3抑制剂LY5对髓母细胞瘤细胞的生物学作用。(3)评价LY5对小鼠髓母细胞瘤模型的体内抑制作用。

 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.