HuR and RNA regulation as a Novel Therapeutic Target in Malignant Glioma

HuR 和 RNA 调控作为恶性胶质瘤的新治疗靶点

• 批准号: 9257249
• 负责人: PETER H KING
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257249
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Angiogenic Factor; Apoptosis; Apoptosis Inhibitor; Apoptotic; Attenuated; BCL2 gene; Binding; Binding Proteins; Biochemical; Biological Assay; Brain Neoplasms; Breast; Cause of Death; Cell Proliferation; Cell Survival; Cell division; Cell physiology; Cells; Central Nervous System Neoplasms; Colon; Colon Carcinoma; Complex; Data; Development; Elements; Family; Funding; Gene Expression Regulation; Genes; Glioblastoma; Glioma; Growth; Hypoxia; Impairment; In Vitro; Inflammation; Interleukin-8; Investigation; Laboratories; Link; Literature; Lung; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Messenger RNA; Molecular; NF-kappa B; Neoplasm Metastasis; Nude Mice; Pathway interactions; Patients; Phenotype; Population; Post-Transcriptional Regulation; Post-Translational Protein Processing; Process; Production; Property; Prostate; RNA; RNA Binding; RNA Splicing; RNA Stability; RNA-Binding Proteins; Radiolabeled; Recombinant Proteins; Regulation; Regulatory Pathway; Reporting; Resistance; Small Interfering RNA; Solid Neoplasm; Specificity; Specimen; Stem cells; TIS11 protein; TNF gene; Testing; Therapeutic; Toxic effect; Translations; Tumor Initiators; Tumor Suppression; Up-Regulation; Vascular Endothelial Growth Factors; Vascular blood supply; Veterans; War; angiogenesis; antitumor effect; attenuation; genetic regulatory protein; in vivo; in vivo Model; inhibitor/antagonist; knock-down; malignant breast neoplasm; mouse model; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; palliative; programs; public health relevance; small molecule inhibitor; stressor; therapeutic target; therapy resistant; transcription factor; treatment strategy; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): A tumor depends upon many cellular processes for growth and survival. Angiogenesis, for example, allows the tumor to create its own vascular supply and thus promotes growth, survival, and metastases. Cell proliferation, on the other hand, leads to sustained cell division and tumor growth. The molecular pathways leading to these processes are multiple, complex, and often redundant. Thus, therapies which have the potential to target different pathways would provide an effective strategy for treatment. RNA stability/translational efficiency is one level of gene regulation which interfaces with many of these pathways. Genes critical for malignant glioma (MG) progression, including growth, angiogenic and anti-apoptotic factors, are regulated at the RNA level by a common motif, the AU-rich element (ARE), present in the 3' untranslated region (UTR). Stressors such as hypoxia, inflammation and tumor therapy are often overcome by upregulation of these genes through RNA stabilization and enhanced translational efficiency. Vascular endothelial growth factor (VEGF), interleukin (IL)- 8, Bcl-2 and other inhibitors of apoptosis (cIAP1 and 2), all of which drive tumor progression in MG are extensively regulated at these levels. ARE-directed post-transcriptional regulation is tightly governed by RNA binding proteins (RBP) that bind to these cis elements. Certain RBPs such as tristetraprolin (TTP) and KH-type splicing regulatory protein (KSRP) bind to the ARE and negatively regulate the mRNA target by accelerating degradation and/or silencing translation. HuR, on the other hand, binds to the same elements but promotes mRNA stabilization and enhanced translation. Since our initial observation of HuR overexpression in MG, there have been multiple reports linking HuR to high grade malignancy and poor prognosis in all of the major solid tumors (e.g. breast, lung, prostate, and colon cancer). In the previous funding cycle, we have demonstrated that HuR is required for malignant glioma growth in vivo. This background provides the rationale for the current proposal which is to investigate the anti-cancer properties of a small molecule inhibitor of HuR (MS444) in malignant glioma. We have exciting in vivo preliminary data showing an anti-cancer effect and no significant toxicity. We also have data indicating that brain tumor initiating cells, normally resistant to standard therapy, are particularly sensitive to the inhibitor. We have found that HuR inhibition may target a critical survival pathway driven by NF-kB. Our hypothesis is that MS444 inhibits glioma growth by disrupting the posttranscriptional regulation of key tumor survival pathways provided by HuR. The specific aims will use authentic primary glioma xenolines and mouse models to further characterize this nascent class (i.e. post- transcriptional regulation) of anti-cancer targets. The common occurrence of ARE-governed RNA regulation of growth and anti-apoptotic factors across many tumors broadens the relevance of this proposal MG. Specific Aims: 1. To characterize the antitumor phenotype of the HuR inhibitor, MS-444, in malignant glioma. 2. To characterize the molecular impact of HuR inhibition on the NF-kB survival pathway in malignant glioma as a mechanism for the anticancer effects of MS444. 3. To assess the specificity of MS444 and other HuR inhibitors for binding to HuR and blocking mRNA binding.

描述（由申请人提供）： 肿瘤的生长和存活取决于许多细胞过程。例如，血管生成允许肿瘤产生自己的血管供应，从而促进生长、存活和转移。另一方面，细胞增殖导致持续的细胞分裂和肿瘤生长。导致这些过程的分子途径是多重的、复杂的，而且常常是多余的。因此，具有针对不同途径的潜力的疗法将提供有效的治疗策略。 RNA 稳定性/翻译效率是基因调控的一个水平，与许多这些途径相互作用。对恶性神经胶质瘤 (MG) 进展至关重要的基因，包括生长、血管生成和抗凋亡因子，在 RNA 水平上受到共同基序（存在于 3' 非翻译区 (UTR) 的富含 AU 元件 (ARE)）的调节。缺氧、炎症和肿瘤治疗等应激源通常可以通过 RNA 稳定和增强的翻译效率上调这些基因来克服。血管内皮生长因子 (VEGF)、白细胞介素 (IL)-8、Bcl-2 和其他细胞凋亡抑制剂 (cIAP1 和 2)，所有这些因子都驱动 MG 肿瘤进展，并在这些水平上受到广泛调节。 ARE 指导的转录后调控受到与这些顺式元件结合的 RNA 结合蛋白 (RBP) 的严格控制。某些 RBP，例如三四脯氨酸 (TTP) 和 KH 型剪接调节蛋白 (KSRP) 与 ARE 结合，并通过加速降解和/或沉默翻译来负调节 mRNA 靶标。另一方面，HuR 与相同的元件结合，但促进 mRNA 稳定并增强翻译。自从我们最初观察到 MG 中 HuR 过度表达以来，已有多份报告将 HuR 与所有主要实体瘤（例如乳腺癌、肺癌、前列腺癌和结肠癌）的高度恶性肿瘤和不良预后联系起来。在上一个资助周期中，我们已经证明 HuR 是体内恶性胶质瘤生长所必需的。这一背景为当前的提案提供了理论依据，即研究 HuR 小分子抑制剂 (MS444) 在恶性神经胶质瘤中的抗癌特性。我们拥有令人兴奋的体内初步数据，显示其具有抗癌作用且无明显毒性。我们还有数据表明，通常对标准治疗有抵抗力的脑肿瘤起始细胞对抑制剂特别敏感。我们发现 HuR 抑制可能针对由 NF-kB 驱动的关键生存途径。我们的假设是，MS444 通过破坏 HuR 提供的关键肿瘤生存途径的转录后调节来抑制神经胶质瘤生长。具体目标将使用真实的原发性神经胶质瘤异种蛋白和小鼠模型来进一步表征这一新生类别（即转录后调控）的抗癌靶标。在许多肿瘤中常见的 ARE 控制的 RNA 对生长和抗凋亡因子的调节拓宽了该提议 MG 的相关性。具体目标： 1. 表征 HuR 抑制剂 MS-444 在恶性神经胶质瘤中的抗肿瘤表型。 2. 表征 HuR 抑制对恶性神经胶质瘤中 NF-kB 存活途径的分子影响，作为 MS444 抗癌作用的机制。 3.评估MS444和其他HuR抑制剂结合HuR并阻断mRNA结合的特异性。