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: 8588570
• 负责人: Amy Beth Heimberger
• 金额: $ 24.51万
• 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/8588570
• 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.

一个关键的转录因子，即转录的信号换能器和激活因子（Stat）3，驱动 恶性神经胶质瘤的肿瘤成分，通常表达过度。磷酸化统计数据 通过增强肿瘤发生，包括神经瘤癌干细胞（GSC）的贡献 增殖，血管生成，侵袭和免疫抑制。我们已经开发了WP1066，这是一种有效的 具有出色的血脑屏障渗透的STAT3的口服抑制剂，显示出标记的 在体内对已建立的脑异质神经胶质瘤的疗效。我们已经证明了 WP1066活性的重要机制是直接抗肿瘤效应和 肿瘤介导的免疫抑制的逆转。在这项拟议的研究中，我们假设 除了直接抑制细胞增殖，血管生成和干性，以P-STAT为目标 小分子抑制剂WP1066导致GBM介导的免疫的治疗显着逆转 抑制导致患者生存的改善。为了检验我们的假设，我们的第一个目标将探讨是否存在 肿瘤的免疫学状态可能会影响对STAT3封锁的反应。这将涉及 使用癌症基因组图集将免疫反应与GBM亚型相关联，然后验证 这些发现具有免疫组织化学和免疫功能测定。这个前提将是正式的 在鼠模型中测试，然后在特定目的2中进行的人类患者测试。鉴于 替莫唑胺在治疗GBM患者中，然后我们将探索治疗作用和免疫 在GSC和鼠模型中，WP1066和Temozolomide的组合的调节 在以后的临床试验中，可能会影响选定的目标患者人群。而且，我们会的 研究是否仅通过控制肿瘤介导的免疫来调查范式转移概念 抑制作用，足够的抗肿瘤免疫可诱导肿瘤清除。成功完成 项目可能会导致一种新的药物，不仅会影响恶性神经胶质瘤患者的生存 还将对其他各种恶性肿瘤进行治疗申请，包括 转移到大脑。 相关性：不要超过提供的空间。 针对针对新型途径的恶性神经膜瘤的新有效疗法的开发 有中枢神经系统恶性肿瘤是一个主要的未满足的临床需求。该提议将测试一部小说， 信号转导和转录激活因子的小分子抑制剂（STAT）-3途径，关键 肿瘤发生和免疫抑制，用于在已建立的中枢神经系统的患者中实施 恶性肿瘤。