Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway

一个关键的转录因子，信号转导和转录激活因子(STAT)3，驱动着 恶性胶质瘤的致瘤成分，通常过度表达。磷酸化STATS 促进肿瘤发生，包括胶质瘤肿瘤干细胞(GSC)的贡献，通过增强 增殖、血管生成、侵袭和免疫抑制。我们已经开发出WP1066，一种强有力的 口服STAT3抑制剂，具有良好的血脑屏障穿透性，显示出明显的 体内对已建立的脑内异质性胶质瘤的疗效。我们已经证明了一个 WP1066的S活性的重要机制是直接抗肿瘤作用和抗肿瘤作用的共同作用。 逆转肿瘤介导的免疫抑制。在这项拟议的研究中，我们假设在 除了直接抑制细胞增殖、血管生成和干细胞分化外，还可以通过靶向p-STATs 小分子抑制剂WP1066在治疗上显著逆转GBM介导的免疫 抑制导致改善患者的存活率。为了检验我们的假设，我们的首要目标是探索 肿瘤的免疫状态可能影响对STAT3阻断的反应。这将涉及到 使用癌症基因组图谱关联GBM亚型的免疫应答，然后验证 这些发现是通过免疫组织化学和免疫功能分析得出的。这一前提将被正式 在小鼠模型上进行测试，然后在人类患者身上进行特定目的的测试2。考虑到 替莫唑胺在治疗GBM患者时，我们将探讨其治疗效果和免疫效果 WP1066和替莫唑胺合用对GSC和小鼠模型的调制作用 在以后的临床试验中，可能会影响选定的目标患者群体。此外，我们还将 研究一种范式转变的概念，即是否通过简单地控制肿瘤介导的免疫 抑制，诱导足够的抗肿瘤免疫，使肿瘤清除。成功完成这项工作 该项目可能导致一种新的药物，不仅可以影响恶性胶质瘤患者的生存，而且 对其他多种恶性肿瘤也有治疗作用，包括 转移到脑部。 相关性：不要超过所提供的空间。 针对相关新途径的恶性胶质瘤新的有效治疗方法的开发 中枢神经系统恶性肿瘤是临床上尚未满足的主要需求。这项提议将测试一部小说， 小分子信号转导和转录激活剂，(STAT)-3途径，关键 肿瘤发生和免疫抑制，用于已建立中枢神经系统的患者 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.