MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm

摘要 广泛的临床前数据支持MAP激酶RAS/RAF/MEK/ERK的相关性 癌症生物学中的信号传导途径及其作为人类癌症治疗靶点的潜力。我们 先前显示，第1代细胞对肿瘤MEK和ERK 1/2磷酸化的抑制作用， MEK和ERK药理学抑制剂（或相关的shRNA敲除）导致显著的细胞死亡 在弥漫性大B细胞淋巴瘤（DLBCL）肿瘤模型中。MCT-1是一种致癌基因， MEK/ERK下游，在大多数原发性DLBCL中组成性过表达 （>95%）（通过免疫组织化学），以及在所有外周T细胞淋巴瘤病例中（100%）。 此外，MCT-1已被证明可诱导细胞增殖并激活细胞存活 通路，而我们小组和其他人以前的工作表明，MCT-1癌基因 通过与密度调节蛋白的结合， 关键癌症相关mRNA的翻译。 我们有强有力的初步数据表明，新的第二代MEK小分子 抑制剂AZD 6244下调pERK和关键底物如MCT-1、c-MYC和MCL-1。 此外，AZD 6244抑制增殖，减少集落形成，并诱导剂量依赖性 DLBCL细胞系，原代细胞， 和人淋巴瘤异种移植模型中。我们有更多令人兴奋的新数据显示， AZD 6244下调pERK并诱导T细胞淋巴瘤细胞中的显著细胞死亡。几 已经开发了抑制MEK/ERK活性用于治疗癌症的策略; 然而，临床上可获得小分子MEK/ERK抑制剂很少。而且他们 从未在非霍奇金淋巴瘤（NHL）中进行过临床研究。在近18年的时间里， 2010年12月，CTEP审查、审查并最终批准/启动了一项临床试验 使用新型小分子MEK抑制剂AZD 6244治疗复发性DLBCL的建议。 这个多PI“团队科学”转化提案的中心假设是， 用单独的新型MEK抑制剂阻断MAP激酶信号传导途径， 与其他新型靶向药物合理联合，将有效抑制NHL 临床前表型（在B细胞和T细胞NHL细胞中，体内NHL SCID异种移植物中，和肿瘤细胞中） 移植物模型），并为NHL患者带来新的治疗范例和有效的治疗。 此外，拟议的研究将调查遗传的分子特征， 网络，包括“翻译概况”，这将从根本上促进我们对 B细胞和T细胞淋巴瘤发生的生物学。

ABSTRACT 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 showed previously that inhibition of tumor MEK and ERK1/2 phosphorylation by 1st generation MEK and ERK pharmacologic inhibitors (or related shRNA knockouts) result in significant 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 majority of primary DLBCLs (>95%) (by immunohistochemistry), as well as in all peripheral T-cell lymphoma cases (100%). Furthermore, MCT-1 has ben shown to induce cel proliferation and activate cell survival pathways, while previous work from our group and others has shown that the MCT-1 oncogene through its association with density-regulated protein interacts with the cap complex and modulates the translation of critical cancer-related mRNAs. We have strong preliminary data showing that the novel 2nd generation MEK small molecule inhibitor, AZD6244, downregulates pERK and key substrates such as MCT-1, c-MYC and MCL-1. Further, AZD6244 inhibited proliferation, decreased colony formation, and induced dose-dependent apoptosis at nanomolar (and 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 significant cell death in T-cell lymphoma cells. Several strategies have been developed to suppress MEK/ERK activity for the treatment of cancer; however, few small-molecule MEK/ERK inhibitors have become clinically available. Moreover, they have never been clinically studied in non-Hodgkin lymphoma (NHL). Over the period of nearly 18 months, CTEP reviewed, vetted, and ultimately approved/activated (December 2010) a clinical trial proposal using the novel small-molecule MEK inhibitor, AZD6244, for relapsed DLBCL. The central hypothesis of this multi-PI "team science" translational proposal is that interruption of the MAP kinase signaling pathway with novel MEK inhibitors alone, and moreover combined together rationally with other novel targeted agents, will effectively repress the NHL phenotype pre-clinically (in B-cell and T-cell NHL cells, in vivo NHL SCID xenografts, and tumor graft models) and result in a new therapeutic paradigm and efficacious therapy for NHL patients. Furthermore, the proposed research will investigate the molecular characterization of genetic networks including 'translational profiles' which will fundamentally advance our understanding of the biology of B-cell and T-cell lymphomagenesis.