Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway

一个关键的转录因子，信号转导子和转录激活子（STAT）3，驱动转录因子的表达。 恶性胶质瘤的致瘤成分，通常过度表达。磷酸化STATS 传播肿瘤发生，包括神经胶质瘤癌症干细胞（GSC）的贡献，通过增强 增殖、血管生成、侵袭和免疫抑制。我们开发了WP 1066，一种有效的 具有优异的血脑屏障渗透性的口服STAT 3抑制剂， 对体内已建立的脑内异质性胶质瘤的有效性。我们已经证明， WP 1066活性的重要机制是直接抗肿瘤作用和 逆转肿瘤介导的免疫抑制。在这项研究中，我们假设，在 除了直接抑制细胞增殖、血管生成和干细胞外，还可以用 小分子抑制剂WP 1066导致治疗上显著逆转GBM介导的免疫应答， 抑制导致改善的患者存活。为了验证我们的假设，我们的第一个目标是探索 肿瘤的免疫状态可能影响对STAT 3阻断的反应。这将涉及 使用癌症基因组图谱将免疫反应与GBM亚型相关联，然后验证 免疫组化和免疫功能测定。这一前提将正式 在小鼠模型中进行测试，然后在Specific Aim 2中在人类患者中进行测试。鉴于必须 替莫唑胺治疗GBM患者，我们将探讨治疗效果和免疫 WP1066和替莫唑胺的组合对GSC和鼠模型内的调节， 可能会影响后续临床试验中选定的目标患者人群。而且还要 研究是否通过简单地控制肿瘤介导的免疫， 当抑制时，诱导足够的抗肿瘤免疫以用于肿瘤清除。成功完成本 该项目可能会产生一种新的药物，不仅可以影响恶性胶质瘤患者的生存， 也可用于治疗多种其他恶性肿瘤，包括那些 转移到脑部 相关性：不要超过所提供的空间。 针对恶性胶质瘤的新的，有效的治疗方法的开发， 中枢神经系统恶性肿瘤的治疗是一个主要的未满足的临床需求。这个提案将测试一部小说， 信号转导和转录激活因子（STAT）-3途径的小分子抑制剂， 肿瘤发生和免疫抑制，用于在已确定CNS患者中实施 恶性肿瘤。

A key transcriptional factor, the signal transducer and activator of transcription (STAT) 3, drives the tumorigenic components of malignant gliomas and is commonly over expressed. Phosphorylated STATS propagates tumorigenesis, including the glioma cancer stem cell (GSC) contribution, by enhancing proliferation, angiogenesis, invasion, and immunosuppression. We have developed WP1066, a potent orally administered inhibitor of STAT3 with excellent blood-brain-barrier penetration that displays marked efficacy against established intracerebral heterogeneous gliomas in vivo. We have demonstrated that a significant mechanism of WP1066's activity is a combination of both direct anti-tumor effects and the reversal of tumor-mediated immune suppression. In this proposed study, we hypothesize that that in addition to directly inhibiting cell proliferation, angiogenesis, and stemness, targeting p-STATS with the small molecule inhibitor WP1066 results in a therapeutically significant reversal of GBM-mediated immune suppression leading to improved patient survival. To test our hypothesis, our first aim will explore whether the immunological status of the tumor might influence the response to STAT3 blockade. This will involve correlating immune responses to GBM subtypes using The Cancer Genome Atlas and then validating these findings with immunohistochemistry and immune functional assays. This premise will be formally tested in murine models and then in human patients in Specific Aim 2. Given the importance of temozolomide in the treatment of GBM patients, we will then explore the therapeutic effects and immune modulation of the combination of WP1066 and temozolomide on the GSC and within murine models, which may influence, the selected targeted patient population during later clinical trials. Moreover, we will investigate a paradigm shifting concept of whether by simply controlling tumor-mediated immune suppression, sufficient anti-tumor immunity is induced for tumor clearance. Successful completion of this project could result in a novel agent that not only could impact the survival of malignant glioma patients but would also have therapeutic application for a wide variety of other malignancies, including those that metastasis to the brain. RELEVANCE: DO NOT EXCEED THE SPACE PROVIDED. The development of new, effective therapies for malignant gliomas that target novel pathways associated with central nervous system malignancies is a major unmet clinical need. This proposal will test a novel, small molecular inhibitor of the signal transduction and activator of transcription, (STAT)-3 pathway, key to tumorigenesis and immune suppression, for implementation in patients with established CNS malignancies.