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。我们之前的研究表明，第一代MEK和ERK药物抑制剂（或shRNA敲低）抑制肿瘤MEK和ERK1/2磷酸化导致弥漫性大B细胞淋巴瘤（DLBCL）肿瘤模型中的细胞死亡。MCT-1是MEK/ERK的直接下游致癌基因，在绝大多数原发性dlbcl（95%）和所有外周t细胞淋巴瘤（100%）中构成性过表达。我们小组之前的工作证实，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核糖体上mrna的装载（翻译谱）。尽管已经开发了几种抑制MAPK信号的策略，但小分子MEK抑制剂代表了迄今为止最特异性和最有效的策略。AZD6244 （ry -142886）是一种新型的第二代小分子MEK拮抗剂。AZD6244的I期和II期临床研究已经在实体肿瘤中完成，然而，这种靶向抗mek药物从未在淋巴瘤中进行过测试。在合作的努力下，Gartenhaus和Evens实验室最近发表的数据显示AZD6244在DLBCL中的显著活性（见：Bhalla S， Evens a，等）。血2011;PMID: 21628402)。我们发现AZD6244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，AZD6244在纳摩尔（临床上可达到的）浓度下抑制增殖，减少集落形成，并诱导剂量依赖性凋亡。我们有更多令人兴奋的新数据显示AZD6244下调pERK并诱导t细胞淋巴瘤的死亡。基于这些临床前研究结果，我们开展了一项研究人员发起的II期试验，研究新型小分子MEK抑制剂，

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.