Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway

用 STAT3 通路的新型抑制剂靶向恶性胶质瘤

• 批准号: 8753979
• 负责人: Amy Beth Heimberger
• 金额: $ 24.53万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8753979
• 关键词: A Mouse; Antigens; Apoptosis; Automobile Driving; Biological Assay; Biopsy; Blood - brain barrier anatomy; Brain; Cell Proliferation; Clinical; Clinical Trials; Data; Development; Epidermal Growth Factor; Glioblastoma; Glioma; Growth; Human; Immune; Immune response; Immune system; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Inflammatory Response; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mesenchymal; Microvascular Proliferation; Modeling; Molecular; Molecular Target; Mus; Natural Immunity; Neoplasm Metastasis; Neuraxis; Pathway interactions; Patients; Penetration; Process; Property; Recurrence; Research Personnel; Resected; STAT3 gene; Signal Transduction Inhibitor; Stat3 protein; Stem cells; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Effect; Transcription Coactivator; Transgenic Organisms; Tumor Antigens; Tumor Immunity; Variant; adaptive immunity; angiogenesis; base; c-myc Genes; cancer stem cell; cancer therapy; cell killing; effective therapy; immunological status; immunoregulation; improved; in vivo; inhibitor/antagonist; neoplastic cell; novel; patient population; preclinical study; prevent; programs; response; small molecule; stemness; success; temozolomide; tumor; tumor microenvironment; tumorigenesis; tumorigenic

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.

信号转导子和转录激活子 (STAT) 3 是一个关键的转录因子，可驱动 恶性神经胶质瘤的致瘤成分，并且通常过度表达。磷酸化统计 通过增强肿瘤发生的传播，包括神经胶质瘤干细胞 (GSC) 的贡献 增殖、血管生成、侵袭和免疫抑制。我们开发了 WP1066，一种有效的 口服 STAT3 抑制剂，具有出色的血脑屏障渗透性，显示显着 对体内已建立的脑内异质神经胶质瘤的功效。我们已经证明了一个 WP1066 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。在这项拟议的研究中，我们假设 除了直接抑制细胞增殖、血管生成和干细胞性外，还针对 p-STATS 小分子抑制剂 WP1066 可显着逆转 GBM 介导的免疫 抑制导致患者生存率提高。为了检验我们的假设，我们的首要目标是探索是否 肿瘤的免疫状态可能会影响对 STAT3 阻断的反应。这将涉及到 使用癌症基因组图谱将免疫反应与 GBM 亚型相关联，然后进行验证 这些发现与免疫组织化学和免疫功能测定有关。这个前提将被正式 在特定目标 2 中先在小鼠模型中进行测试，然后在人类患者中进行测试。鉴于 替莫唑胺治疗GBM患者，我们将探讨其治疗效果和免疫情况 WP1066 和替莫唑胺组合对 GSC 和小鼠模型的调节， 可能会影响后期临床试验中选定的目标患者群体。此外，我们将 研究范式转变的概念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力以清除肿瘤。顺利完成本次 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，而且可以 也可用于治疗多种其他恶性肿瘤，包括那些 转移至脑部。 相关性：请勿超出所提供的空间。 针对恶性神经胶质瘤的新的有效疗法的开发，其目标是相关的新途径 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。该提案将测试一部小说， 信号转导和转录激活剂 (STAT)-3 途径的小分子抑制剂，是 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。