MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm

描述（由申请人提供）：大量临床前数据支持MAP激酶RAS/RAF/MEK/ERK信号通路在癌症生物学中的相关性及其作为人类癌症治疗靶点的潜力。我们先前表明，在弥漫性大B细胞淋巴瘤（DLBCL）肿瘤模型中，第一代MEK和ERK药理学抑制剂（或shRNA敲低）对肿瘤MEK和ERK 1/2磷酸化的抑制导致细胞死亡。MCT-1是一种紧邻MEK/ERK下游的癌基因，在绝大多数原发性DLBCL（>95%）以及所有外周T细胞淋巴瘤（100%）中组成性过表达。我们小组以前的工作确定了ERK对MCT-1的磷酸化对于MCT-1蛋白的稳定及其促进细胞增殖的能力至关重要。值得注意的是，我们已经证明MCT-1可以改变淋巴瘤细胞中多聚核糖体上mRNA的装载（翻译谱）。尽管已经开发了几种策略来抑制MAPK信号传导，但小分子MEK抑制剂代表了迄今为止最特异和有效的策略。 AZD 6244（ARRY-142886）是一种新型的第二代小分子MEK拮抗剂。研究AZD 6244的I期和II期临床研究已在实体瘤中完成，然而，这种靶向抗MEK药物从未在淋巴瘤中进行过测试。在合作努力中，Gartenhaus和Evens实验室最近发表的数据证明了AZD 6244在DLBCL中的显著活性（参见：Bhalla S，Evens A，et al. Blood 2011; PMID：21628402）。我们发现AZD 6244下调pERK和关键底物包括MCT-1，c-MYC和MCL-1。此外，在DLBCL细胞系、原代细胞和人淋巴瘤异种移植模型中，AZD 6244在纳摩尔（临床可达到）浓度下抑制增殖、减少集落形成并诱导剂量依赖性细胞凋亡。我们有其他令人兴奋的新数据显示，AZD 6244下调pERK并诱导T细胞淋巴瘤死亡。基于这些临床前的发现，我们已经开发了一项由兴奋剂启动的II期试验来研究新型小分子MEK抑制剂， AZD 6244，用于复发性/难治性DLBCL患者。本试验由CTEP审查和批准; CTEP将提供和分发药物。此外，我们将与芝加哥大学N 01 II期联盟合作，进行研究协调和患者招募。 这种多PI“团队科学”翻译建议的中心假设是，单独使用新型MEK抑制剂和/或与其他新型靶向药物合理组合（即，NF 8B抑制剂、双重PI 3 K/AKT抑制剂、mTOR抑制剂）将在临床前有效地抑制B细胞和T细胞NHL细胞、体内SCID异种移植物和肿瘤移植物模型中的淋巴瘤表型。此外，这将代表用于治疗淋巴瘤的新的治疗范例。此外，拟议的研究将通过询问翻译谱来研究遗传网络的分子特征， 这将从根本上推进我们对淋巴瘤生物学的理解。 公共卫生相关性：总的来说，拟议的工作是创新的，因为它利用了一种翻译和靶向治疗非霍奇金淋巴瘤（NHL）的方法，这已经被我们的小组仔细研究过。基于我们研究NHL中MAP激酶的小组的广泛临床前数据，我们开发了一项临床试验来测试NHL中的这种治疗模式。我们期望由此产生的研究将确定一种新的NHL治疗方法。单独或合理组合使用抗MEK抑制剂靶向关键的NHL相关激酶提供了验证MAP激酶信号传导在NHL中的重要性的方法。这些结果将是创新的，因为它们有望为B细胞和T细胞NHL提供新的治疗方法。此外，预计这些结果将从根本上推进我们对B细胞和T细胞淋巴瘤发生的理解。

DESCRIPTION (provided by applicant): Extensive preclinical data supports the relevance of the MAP kinase RAS/RAF/MEK/ERK signaling pathway in cancer biology and its potential as a therapeutic target in human cancers. We previously showed that inhibition of tumor MEK and ERK1/2 phosphorylation by 1st generation MEK and ERK pharmacologic inhibitors (or shRNA knockdowns) resulted in cell death in diffuse large B- cell lymphoma (DLBCL) tumor models. MCT-1, an oncogene immediately downstream of MEK/ERK is constitutively over expressed in the vast majority of primary DLBCLs (>95%), as well as in all peripheral T-cell lymphoma (100%). Previous work from our group established that phosphorylation of MCT-1 by ERK is critical for stabilization of MCT-1 protein and for its ability to promote cell proliferation. Significantly, MCT-1 has been shown by us to alter loading of mRNAs on polyribosomes (translational profile) in lymphoma cells. Although several strategies have been developed to suppress MAPK signaling, small molecule MEK inhibitors represent the most specific and effective strategy to date. AZD6244 (ARRY-142886) is a novel 2nd generation small molecule MEK antagonist. Phase I and II clinical studies studying AZD6244 have been completed in solid tumors, however, this targeted anti-MEK agent has never been tested in lymphoma. In a collaborative effort, the Gartenhaus and Evens laboratories recently published data demonstrating the significant activity of AZD6244 in DLBCL (see: Bhalla S, Evens A, et al. Blood 2011; PMID: 21628402). We showed that AZD6244 down-regulated pERK and key substrates including MCT-1, c-MYC and MCL-1. Further, AZD6244 inhibited proliferation, decreased colony formation, and induced dose-dependent apoptosis at nanomolar (clinically achievable) concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model. We have additional exciting new data showing that AZD6244 downregulates pERK and induces death in T-cell lymphoma. Based on these pre-clinical findings, we have developed an investigator-initiated phase II trial to study the novel small-molecule MEK inhibitor, AZD6244, for patients with relapsed/refractory DLBCL. This trial was vetted and approved by CTEP; CTEP will supply and distribute drug. Furthermore, we will collaborate with the University of Chicago N01 Phase II consortium for study coordination and patient accrual. The central hypothesis of this multi-PI "team science" translational proposal is that interruption of the MAP kinase signaling pathway with a novel MEK inhibitor alone, and/or combined rationally with other novel targeted agents (i.e., NF8B inhibitor, dual PI3K/AKT inhibitor, mTOR inhibitor), will effectively repress the lymphoma phenotype pre-clinically in B-cell and T-cell NHL cells, in vivo SCID xenografts, and tumor graft models. Further, this will represent a new therapeutic paradigm for the treatment of lymphoma. In addition, the proposed research will investigate the molecular characterization of genetic networks through the interrogation of translational profiles, which will fundamentally advance our understanding of the biology of lymphomagenesis. PUBLIC HEALTH RELEVANCE: Overall, the proposed work is innovative because it capitalizes on a translational and targeted means of treating non-Hodgkin's lymphoma (NHL), which has been examined closely by our groups. Based on extensive pre-clinical data by our groups investigating MAP kinase in NHL, we developed a clinical trial to test this therapeutic paradigm in NHL. It is our expectation that the resultant research will identify a new therapy for NHL. Use of anti-MEK inhibitors alone, or in rational combinations, to target critical NHL-related kinases provides the means for validating the importance of MAP kinase signaling in NHL. These results will be innovative, because they are expected to provide a new treatment for B-cell and T-cell NHL. In addition, it is expected that the results will fundamentally advance our understanding of B-cell and T-cell lymphomagenesis.