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）： 肿瘤取决于许多细胞过程的生长和存活。例如，血管生成使肿瘤能够创建自己的血管供应，从而促进生长，生存和转移。另一方面，细胞增殖会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，复杂的且通常是冗余的。因此，有可能靶向不同途径的疗法将为治疗提供有效的策略。 RNA稳定性/转化效率是基因调控的一个水平，它与许多此途径相连。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水平上通过共同基序（富含AU富元素）在RNA水平上调节，这是3'未翻译区域（UTR）中的。通过RNA稳定和提高的转化效率，通常克服这些基因，例如缺氧，炎症和肿瘤治疗等应激源。血管内皮生长因子（VEGF），白介素（IL）-8，Bcl-2和其他凋亡的抑制剂（CIAP1和2），所有这些驱动MG中肿瘤进展均在这些水平上受到广泛调节。指导的转录后调节受RNA结合蛋白（RBP）的紧密控制，该蛋白（RBP）与这些CIS元素结合。某些RBP，例如Tristraprolin（TTP）和KH型剪接调节蛋白（KSRP）与AS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与相同的元素结合，但促进了mRNA稳定和增强的翻译。自从我们最初观察到MG中的HUR过表达以来，已经有多个报道将HUR与所有主要实体瘤（例如乳腺癌，肺，前列腺和结肠癌）联系起来的高年级恶性肿瘤和预后不良。在上一个融资周期中，我们证明了HUR是体内恶性神经胶质瘤生长所必需的。该背景为当前建议提供了基本原理，该提议是为了研究恶性神经胶质瘤中HUR（MS444）的小分子抑制剂的抗癌特性。我们有令人兴奋的体内初步数据，显示了抗癌作用，没有显着的毒性。我们还拥有数据表明，通常对标准治疗具有抗药性的脑肿瘤引发细胞对抑制剂特别敏感。我们发现，HUR抑制可能针对NF-KB驱动的关键生存途径。我们的假设是MS444通过破坏HUR提供的关键肿瘤存活途径的转录后调节来抑制神经胶质瘤的生长。具体目的将使用正宗的原发性神经胶质瘤和小鼠模型来进一步表征抗癌靶标的新生阶层（即转录后调节）。在许多肿瘤中，生长和抗凋亡因子的RNA调节的常见发生范围扩大了该提案MG的相关性。具体目的：1。表征恶性神经胶质瘤中HUR抑制剂MS-444的抗肿瘤表型。 2。为了表征HUR抑制对恶性神经胶质瘤NF-KB存活途径的分子影响，这是MS444抗癌作用的机制。 3。评估MS444和其他HUR抑制剂的特异性，以与HUR结合和阻断mRNA结合。