MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm

描述(申请人提供)：广泛的临床前数据支持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。我们先前的研究表明，在弥漫性大B细胞淋巴瘤(DLBCL)肿瘤模型中，第一代MEK和ERK药物抑制剂(或shRNA敲除)抑制肿瘤MEK和ERK1/2的磷酸化导致细胞死亡。MCT-1是一种紧邻MEK/ERK下游的癌基因，在绝大多数原发DLBCL(95%)以及所有外周T细胞淋巴瘤(100%)中呈结构性过度表达。我们课题组以前的工作证实，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是至关重要的。值得注意的是，我们已经证明MCT-1改变了淋巴瘤细胞中多聚核糖体(翻译图谱)上的mRNAs负荷。虽然已经开发了几种策略来抑制MAPK信号转导，但小分子MEK抑制剂是迄今为止最特异和有效的策略。AZD6244(ARRY-142886)是一种新型的第二代小分子肌醇激酶拮抗剂。研究AZD6244的I期和II期临床研究已经在实体瘤中完成，然而，这种靶向的抗MEK药物从未在淋巴瘤中进行过测试。在一项合作努力中，Gartenhaus和Evens实验室最近公布了AZD6244在DLBCL中的显著活性的数据(见：巴拉·S，Evens A等人)。血液2011年；PMID：21628402)。我们发现AZD6244下调了PERK和关键底物，包括MCT-1，c-MYC和MCL-1。此外，在DLBCL细胞系、原代细胞和人类淋巴瘤异种移植模型中，AZD6244在纳摩尔(临床上可以达到的)浓度下抑制DLBCL细胞的增殖，减少克隆形成，并诱导剂量依赖的凋亡。我们有更多令人兴奋的新数据表明，AZD6244下调了T细胞淋巴瘤中PERK的表达并诱导其死亡。基于这些临床前研究结果，我们开发了一项由研究人员发起的II期试验，以研究新型小分子MEK抑制剂， AZD6244，用于复发/难治性DLBCL患者。这项试验由CTEP审查和批准；CTEP将供应和分发药物。此外，我们将与芝加哥大学N01第二阶段财团合作，以进行研究协调和患者收益。这一多PI“团队科学”翻译建议的中心假设是，单独使用一种新的MEK抑制剂来阻断MAP激酶信号通路，和/或与其他新的靶向药物(即NF8B抑制剂、双重PI3K/AKT抑制剂、mTOR抑制剂)合理结合，将有效地抑制临床前B细胞和T细胞NHL细胞、体内SCID异种移植和肿瘤移植模型中的淋巴瘤表型。此外，这将为淋巴瘤的治疗提供一个新的治疗模式。此外，拟议的研究将通过询问翻译图谱来调查遗传网络的分子特征， 这将从根本上促进我们对淋巴肿大生物学的理解。

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.