MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm

淋巴瘤中的 MAP 激酶信号转导：一种新的治疗范式

• 批准号: 8373276
• 负责人: Andrew M Evens
• 金额: $ 37.35万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373276
• 关键词: Address; Apoptosis; B-Lymphocytes; Biological Markers; Biology; Bioluminescence; Blood; Cancer Biology; Cancer Therapy Evaluation Program; Cell Death; Cell Line; Cell Proliferation; Cells; Cessation of life; Chicago; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Complex; Conduct Clinical Trials; Data; Dose; Exposure to; Gene Targeting; Generations; Genetic; Genetic Translation; Grant; Hodgkin Disease; Human; Hydrogen; Image; Immunoblotting; Inorganic Sulfates; Interruption; Knock-out; Laboratories; Letters; Luciferases; Lymphoma; Lymphomagenesis; MAP Kinase Gene; MAP Kinase Modules; MAP Kinase Signaling Pathways; MAPK3 gene; MCT-1 gene; MEK inhibition; MEKs; Malignant Neoplasms; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; Non-Hodgkin' s Lymphoma; Oncogenes; PI3K/AKT; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Phosphorylation; Phosphotransferases; Polyribosomes; Primary Neoplasm; Proteins; Protocols documentation; Publishing; Refractory; Relapse; Research; Research Personnel; Resistance; Retroviridae; Sampling; Science; Signal Pathway; Signal Transduction; Solid Neoplasm; T-Cell Lymphoma; T-Lymphocyte; Testing; Therapeutic; Transfection; Translational Research; Translations; Universities; Unspecified or Sulfate Ion Sulfates; Work; Xenograft Model; Xenograft procedure; base; clinical efficacy; density; effective therapy; expectation; in vivo; inhibitor/antagonist; innovation; large cell Diffuse non-Hodgkin' s lymphoma; mTOR Inhibitor; mouse model; novel; novel therapeutics; pre-clinical; response; small hairpin RNA; small molecule; therapeutic target; translational clinical trial; tumor; tumor xenograft

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.

描述（由申请人提供）：大量的临床前数据支持 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。我们之前表明，第一代 MEK 和 ERK 药物抑制剂（或 shRNA 敲低）抑制肿瘤 MEK 和 ERK1/2 磷酸化会导致弥漫性大 B 细胞淋巴瘤 (DLBCL) 肿瘤模型中的细胞死亡。 MCT-1 是 MEK/ERK 下游的致癌基因，在绝大多数原发性 DLBCL (>95%) 以及所有外周 T 细胞淋巴瘤 (100%) 中持续过度表达。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，我们已证明 MCT-1 可以改变淋巴瘤细胞中多聚核糖体上 mRNA 的负载（翻译谱）。尽管已经开发出多种策略来抑制 MAPK 信号传导，但小分子 MEK 抑制剂代表了迄今为止最特异、最有效的策略。 AZD6244 (ARRY-142886) 是一种新型第二代小分子 MEK 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，这种靶向抗MEK药物从未在淋巴瘤中进行过测试。在合作中，Gartenhaus 和 Evens 实验室最近发表的数据证明了 AZD6244 在 DLBCL 中的显着活性（参见：Bhalla S、Evens A 等人的 Blood 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，AZD6244 在纳摩尔（临床可实现）浓度下抑制 DLBCL 细胞系、原代细胞和人淋巴瘤异种移植模型中的增殖、减少集落形成并诱导剂量依赖性细胞凋亡。我们还有更多令人兴奋的新数据表明 AZD6244 下调 pERK 并诱导 T 细胞淋巴瘤死亡。基于这些临床前发现，我们开发了一项由研究者发起的 II 期试验来研究新型小分子 MEK 抑制剂， AZD6244，用于复发/难治性 DLBCL 患者。本次试验得到CTEP的审查和批准； CTEP 将供应和分发药品。此外，我们将与芝加哥大学 N01 II 期联盟合作进行研究协调和患者应计。 这一多 PI“团队科学”转化提案的中心假设是，单独使用新型 MEK 抑制剂和/或与其他新型靶向药物（即 NF8B 抑制剂、双重 PI3K/AKT 抑制剂、mTOR 抑制剂）合理组合来中断 MAP 激酶信号通路，将有效抑制临床前 B 细胞和 T 细胞 NHL 细胞、体内 SCID 异种移植物和肿瘤移植模型。此外，这将代表淋巴瘤治疗的新治疗范例。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， 这将从根本上增进我们对淋巴瘤发生生物学的理解。 公共健康相关性：总体而言，拟议的工作具有创新性，因为它利用了治疗非霍奇金淋巴瘤（NHL）的转化和靶向方法，我们的团队对此进行了仔细研究。基于我们研究 NHL MAP 激酶的小组的大量临床前数据，我们开发了一项临床试验来测试 NHL 中的这种治疗模式。我们期望最终的研究能够找到一种治疗 NHL 的新疗法。单独或合理组合使用抗 MEK 抑制剂来靶向关键的 NHL 相关激酶，为验证 MAP 激酶信号转导在 NHL 中的重要性提供了方法。这些结果将具有创新性，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，预计该结果将从根本上增进我们对 B 细胞和 T 细胞淋巴瘤发生的理解。