Novel therapies for Mantle Cell Lymphoma: targets, mechanisms, and prognosis

套细胞淋巴瘤的新疗法：靶点、机制和预后

• 批准号: 9572280
• 负责人: adrian u wiestner
• 金额: $ 25.75万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9572280
• 关键词: Agammaglobulinaemia tyrosine kinase; Antioxidants; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Biological Markers; Blood; Bone Marrow; Bortezomib; Cell Line; Cells; Characteristics; Clinical; Combined Modality Therapy; Correlative Study; Data; Drug resistance; Event; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; Genes; Genetic Polymorphism; In complete remission; Lead; Lymphoid Tissue; Lymphoma; Maintenance; Malignant Neoplasms; Mantle Cell Lymphoma; Mature B-Lymphocyte; Measures; Molecular; Mutation; Non-Hodgkin' s Lymphoma; Pathway interactions; Patients; Prior Therapy; Progression-Free Survivals; Proteasome Inhibition; Proteasome Inhibitor; Randomized; Receptor Activation; Receptor Cell; Receptor Signaling; Receptors, Antigen, B-Cell; Recurrent disease; Refractory; Regimen; Research Personnel; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Stress; Systems Biology; Testing; Treatment Efficacy; Tumor Biology; Up-Regulation; Velcade; improved; in vitro Model; in vivo; inhibitor/antagonist; kinase inhibitor; lymph nodes; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutics; outcome forecast; relapse patients; resistance mechanism; response; rituximab; treatment response; tumor

Mantle cell lymphoma (MCL) is a mature B-cell Non-Hodgkin-Lymphoma that involves the lymphoid tissues, gastrointestinal tract, blood, and bone marrow. MCL is responsive to chemoimmunotherapy but most patients relapse within a few years. Thus MCL has a relatively short median overall survival of 5-7 years, which is amongst the shortest of all B-cell lymphomas. Bortezomib (Velcade) induces responses in 30-50% of patients with relapsed disease and is equally effective in patients sensitive or refractory to prior therapy. To investigate whether the addition of bortezomib to standard chemoimmunotherapy could improve the depth of response and extend the progression free survival we initiated a single center study combining bortezomib with the EPOCH-Rituximab regimen (trial registered as NCT00131976; lead investigator Wyndham Wilson, NCI). For the first cycle bortezomib was given as single agent on day 1, 4, 8, 11 followed by 6 cycles of combination therapy with bortezomib on day 1 and 4 of 21 day cycles. Of the first 38 patients, 63% achieved a complete response, 29% a PR and 3 (8%) did not respond. Responding patients are randomized to maintenance bortezomib for up to 18 months or observation. The trial is ongoing and we continue to collect samples for further analysis correlative studies focused on the effect of bortezomib single agent. We use gene expression profiling to systematically study the effect of proteasome inhibition on the tumor biology of MCL. We hypothesized that resistant tumors preferentially upregulate homeostatic responses to survive proteasome inhibition. Surprisingly, we found the opposite: sensitive tumors strongly upregulated anti-oxidant genes, and proteasome components, while resistant cells showed minimal gene expression changes in response to bortezomib. Furthermore, we found that increased expression of anti-oxidant genes in unstressed cells correlated with decreased sensitivity to proteasome inhibition. To further investigate the mechanisms of bortezomib resistance we generated an in vitro model of bortezomib-adapted MCL cell lines that were 40-80 fold less sensitive to bortezomib than the parental cells. These bortezomib resistant sublines showed increased proteasome activity, survived at lower proteasome capacity and showed characteristics of plasmacytic differentiation. Fresh tumor cells from MCL patients with poor clinical response to bortezomib also expressed plasmacytic features. Additional studies support the conclusion that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition and thus identify possible targets to enhance the therapeutic efficacy of proteasome inhibitors. The efficacy of ibrutinib, a Brutons tyrosine kinase inhibitor, in mantle cell lymphoma (MCL) contradicts the notion that MCL is a malignancy of nave B-cells. However, the role of B-cell receptor (BCR) signaling in MCL remains ill-defined. To interrogate the signaling pathways in MCL in vivo, we profiled gene expression in tumor samples concomitantly isolated from blood and lymph nodes. Expression data identified upregulation of BCR and NF-B signaling proliferation in lymph node-resident MCL cells compared to circulating cells. Activation of relevant signaling molecules in the lymph node confirmed the gene expression data. A subset of leukemic samples had apparent cell-autonomous BCR activation, and carried mutations and/or polymorphism in genes encoding pathway-specific regulatory molecules that may confer ibrutinib resistance. We found direct in vivo evidence for activation of the BCR and canonical NF-B pathways in MCL that, in the absence of activating mutations, depends upon the lymph node microenvironment. These findings provide a mechanistic explanation for the surprising efficacy of ibrutinib in treating this type of lymphoma. Mutations and single nucleotide polymorphisms in components of the BCR and NF-B pathways are associated with cell-autonomous signaling and influence the sensitivity of MCL cells to BCR signaling inhibitors.

地幔细胞淋巴瘤（MCL）是一个成熟的B细胞非霍奇金 - 淋巴瘤，涉及淋巴组织，胃肠道，血液和骨髓。 MCL对化学免疫疗法有反应，但大多数患者在几年内复发。因此，MCL的总中位生存期相对较短，为5 - 7年，这是所有B细胞淋巴瘤中最短的。硼替佐米（Velcade）诱导30-50％复发性疾病患者的反应，并且对患者对先前治疗的敏感或难治性同样有效。为了研究将硼替佐米添加到标准的化学免疫疗法中是否可以改善反应深度并扩展无进展的生存，我们开始了将硼替佐米与Epoch-Rituximab方案相结合的单个中心研究（试用为NCT00131976；首席研究员Wyndham Wilson，NCI）。对于第一个循环，在第1、4、8、11中将硼替佐米作为单一药物，然后在21天周期的第1天和第4天用硼替佐米进行6个循环。在前38名患者中，有63％的患者达到了完全反应，29％的PR和3（8％）没有反应。反应的患者被随机用于维持硼替佐米长达18个月或观察。该试验正在进行中，我们继续收集样本进行进一步分析的相关研究，该研究集中在硼替佐米单一药物的影响上。我们使用基因表达分析来系统地研究蛋白酶体抑制对MCL肿瘤生物学的影响。我们假设耐药性肿瘤优先上调稳态反应，以生存于蛋白酶体抑制作用。令人惊讶的是，我们发现相反：敏感肿瘤强烈上调抗氧化剂基因和蛋白酶体成分，而抗性细胞显示出对硼替佐米的响应的最小基因表达变化。此外，我们发现，在无重理细胞中抗氧化基因的表达增加与对蛋白酶体抑制的敏感性降低相关。为了进一步研究硼替佐米抗性的机制，我们产生了一种体外模型的硼替佐米适应的MCL细胞系，其对硼替佐米的敏感性低于亲本细胞。这些硼替佐米的抗性子宫盐显示出蛋白酶体的活性增加，以较低的蛋白酶体能力存活，并显示出浆细胞分化的特征。来自MCL临床反应不良的MCL患者的新鲜肿瘤细胞也表达了浆细胞特征。其他研究支持以下结论：在没有增加分泌负荷的情况下，浆细胞分化可以使细胞承受蛋白酶体抑制的应力，从而确定可能的靶标，以增强蛋白酶体抑制剂的治疗功效。 地幔细胞淋巴瘤（MCL）中伊布鲁替尼（Brutons酪氨酸激酶抑制剂）的疗效与MCL是Have B细胞的恶性肿瘤相矛盾。但是，B细胞受体（BCR）信号在MCL中的作用仍然不明显。为了询问MCL在体内的信号传导途径，我们在肿瘤样品中介绍了基因表达，并从血液和淋巴结中伴有分离。与循环细胞相比，表达数据鉴定出淋巴结驻留的MCL细胞中BCR和NF-B信号传导增殖的上调。淋巴结中相关信号分子的激活证实了基因表达数据。白血病样品的一部分具有明显的细胞自主性BCR激活，并在编码可能赋予依布鲁替尼耐药性的途径特异性调节分子的基因中携带突变和/或多态性。我们发现了MCL中BCR和规范NF-B途径激活的直接体内证据，在没有激活突变的情况下，它取决于淋巴结微环境。这些发现为ibrutinib在治疗这种类型的淋巴瘤方面具有令人惊讶的功效提供了一种机械解释。 BCR和NF-B途径成分中的突变和单核苷酸多态性与细胞自主信号传导有关，并影响MCL细胞对BCR信号抑制剂的敏感性。