MEK/ERK pathways and MCT-1 in Diffuse Large B-cell Lymphoma

弥漫性大 B 细胞淋巴瘤中的 MEK/ERK 通路和 MCT-1

• 批准号: 8244946
• 负责人: Ronald B Gartenhaus
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244946
• 关键词: 5' Untranslated Regions; Adult; Adverse effects; Aging; American Cancer Society; Apoptosis; Apoptotic; B-Lymphocytes; Biological; Cell Line; Cell Survival; Cells; Clinical; Complex; Development; Diagnosis; Dose; Elderly; Exposure to; Family; Generations; Genes; Genetic; Human; In Vitro; Incidence; Interruption; Laboratories; Link; Lymphoma; Lymphomagenesis; MCT-1 gene; MEK inhibition; MEKs; Malignant Neoplasms; Messenger RNA; Modeling; Molecular; Mutate; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Peptide Initiation Factors; Persons; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Primary Neoplasm; Process; Protein Biosynthesis; Proteins; Pseudouridine; Publications; RNA; Recruitment Activity; Research; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Structure; Therapeutic; Toxic effect; Translation Initiation; Translational Regulation; Translations; Tumor Suppressor Genes; Untranslated Regions; Veterans; Work; Xenograft Model; Xenograft procedure; addiction; archaeosine; chemotherapy; clinically relevant; density; genetic analysis; genetic regulatory protein; improved; in vivo; inhibitor/antagonist; innovation; knock-down; large cell Diffuse non-Hodgkin' s lymphoma; mRNA Differential Displays; mortality; next generation; novel; overexpression; protein function; protein protein interaction; public health relevance; research study; response; small molecule; tumor

DESCRIPTION (provided by applicant): Translation initiation is known to be a common downstream target of signal transduction pathways deregulated in cancer and initiated by mutated/overexpressed oncogenes and tumor suppressors. There is a growing body of evidence linking deregulated translation on the causal pathway to cancer. Therefore, it is reasonable to assume that the downstream translation step provides a major contribution to tumorgenesis induced by activated oncogenic pathways and that this oncogenic addiction may serve as an "Achilles heel" in the treatment of malignancies. MCT-1, an oncogene involved in translational regulation has recently been shown by the Gartenhaus laboratory to be overexpressed in the vast majority of primary diffuse large B-cell lymphomas (DLBCL). Knocking down MCT-1 protein levels in DLBCL significantly reduced cell viability through an apoptotic mechanism, providing the first direct genetic evidence that interfering with MCT-1 function was able to induce apoptosis in lymphoma cells with high endogenous levels of MCT-1 protein. MCT-1 protein interacts with the cap complex, which recruits Density Regulated Protein (DENR) protein, containing an SUI1 domain. The recruitment of DENR has been shown to increase the translation initiation of a subset of mRNAs (translatome), containing a long and highly structured 5' UTR, typically found in cancer related messages. While there are no specific small molecule inhibitors that can directly inhibit MCT-1 at present, its activity has been shown to be regulated by MEK/ERK kinases. Previous work from our group has shown that MCT-1 physically associates with ERK and that disruption of this protein-protein interaction provides a novel targeted approach to treat DLBCL. Furthermore, inhibition of MEK/ERK blocks the phosphorylation and biological activity of MCT-1, further establishing the functional interaction between MCT-1 and the MEK/ERK pathway. Several strategies have been developed to suppress MEK/ERK, however few small-molecule MEK inhibitors have become clinically available. Moreover, this strategy has never been extensively evaluated in lymphoma. We currently have full access to a selective and potent 2nd generation small-molecule MEK inhibitor, AZD-6244. This presents a unique opportunity to target a translational regulatory protein critical to lymphomagenesis. The objective of this application is to investigate the importance of the MEK/ERK pathway and the associated interaction(s) with MCT-1 towards B-cell lymphomagenesis in vitro and in vivo tumor models. The central hypothesis of this proposal is that the MEK/ERK signaling plays a critical role in regulating the stability and activity of the MCT-1 protein in DLBCL and that interruption of MEK/ERK/MCT-1 function with a novel targeted MEK inhibitor will effectively repress the lymphoma phenotype. Furthermore, the molecular characterization of the genetic networks of DLBCL will help us to understand how perturbation of MEK/ERK/MCT-1 regulated genes contributes to lymphomagenesis. The rationale for the proposed research is that MCT-1 and the MEK/ERK pathway have been shown to be important survival pathways in lymphoma and that newer more potent small-molecule MEK inhibitors are now available. We have shown in preliminary experiments that the selective MEK inhibitor, AZD-6244, inhibited proliferation and induced dose-dependent apoptosis at nanomolar concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model. PUBLIC HEALTH RELEVANCE: The American Cancer Society estimates that 66,120 persons were diagnosed with NHL in 2008, and 19,160 died from lymphoma. Lymphomas are increasing in incidence especially in the elderly, a major segment of our current VA population. Unfortunately, despite aggressive chemotherapy mortality is greater than 50% and is associated with significant toxicity. Our understanding of the fundamental processes for this malignancy is limited at present and impedes the rational development of targeted therapies, which can improve response rates while reducing toxicities. The MCT-1 oncogene was recently shown to be overexpressed in the vast majority of the most common lymphoma in adults, DLBCL. Identifying and targeting the kinases that specifically regulate MCT-1 function offers the hope of fewer side effects while improving clinical outcomes in our aging veteran population.

描述（由申请人提供）： 已知翻译起始是癌症中失调的信号转导途径的常见下游靶标，并且由突变/过表达的癌基因和肿瘤抑制因子起始。越来越多的证据表明，翻译失调与癌症的因果关系有关。因此，可以合理地假设下游翻译步骤对由激活的致癌途径诱导的肿瘤发生提供了主要贡献，并且这种致癌成瘾可能作为恶性肿瘤治疗中的“阿喀琉斯之踵”。MCT-1是一种参与翻译调控的癌基因，最近已被Gartenhaus实验室证明在绝大多数原发性弥漫性大B细胞淋巴瘤（DLBCL）中过表达。敲低DLBCL中的MCT-1蛋白水平通过凋亡机制显著降低细胞活力，这提供了第一个直接遗传学证据，即干扰MCT-1功能能够诱导具有高内源性MCT-1蛋白水平的淋巴瘤细胞凋亡。MCT-1蛋白与帽复合物相互作用，该帽复合物募集含有SUI 1结构域的密度调节蛋白（DENR）蛋白。已经显示，DENR的募集增加了mRNA（translatome）的子集的翻译起始，所述mRNA（translatome）含有长且高度结构化的5' UTR，通常在癌症相关信息中发现。虽然目前没有特异性小分子抑制剂可以直接抑制MCT-1，但其活性已被证明受MEK/ERK激酶调节。我们小组以前的工作表明，MCT-1与ERK物理相关，这种蛋白质-蛋白质相互作用的破坏提供了一种治疗DLBCL的新靶向方法。此外，MEK/ERK的抑制阻断了MCT-1的磷酸化和生物活性，进一步建立了MCT-1与MEK/ERK通路之间的功能性相互作用。已经开发了几种策略来抑制MEK/ERK，然而很少有小分子MEK抑制剂在临床上可用。此外，这种策略从未在淋巴瘤中进行过广泛评估。目前，我们完全可以获得选择性和有效的第二代小分子MEK抑制剂AZD-6244。这提供了一个独特的机会来靶向对淋巴瘤发生至关重要的翻译调节蛋白。本申请的目的是在体外和体内肿瘤模型中研究MEK/ERK通路以及与MCT-1的相关相互作用对B细胞淋巴瘤发生的重要性。该提议的中心假设是MEK/ERK信号传导在调节DLBCL中MCT-1蛋白的稳定性和活性中起关键作用，并且用新型靶向MEK抑制剂中断MEK/ERK/MCT-1功能将有效抑制淋巴瘤表型。此外，DLBCL遗传网络的分子特征将有助于我们了解MEK/ERK/MCT-1调控基因的扰动如何促进淋巴瘤的发生。这项研究的基本原理是，MCT-1和MEK/ERK通路已被证明是淋巴瘤中重要的生存途径，并且现在已有更新的更有效的小分子MEK抑制剂。我们已经在初步实验中表明，选择性MEK抑制剂AZD-6244在DLBCL细胞系、原代细胞和人淋巴瘤异种移植模型中以纳摩尔浓度抑制增殖并诱导剂量依赖性凋亡。 公共卫生相关性： 美国癌症协会估计，2008年有66，120人被诊断患有NHL，19，160人死于淋巴瘤。淋巴瘤的发病率正在增加，特别是在老年人中，这是我们目前VA人群的主要部分。不幸的是，尽管有积极的化疗，死亡率仍大于50%，并与显著的毒性相关。目前，我们对这种恶性肿瘤的基本过程的理解是有限的，这阻碍了靶向治疗的合理发展，靶向治疗可以提高反应率，同时降低毒性。最近发现MCT-1癌基因在绝大多数成人最常见的淋巴瘤DLBCL中过表达。识别和靶向特异性调节MCT-1功能的激酶，有望减少副作用，同时改善我们老年退伍军人群体的临床结局。