Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review.
Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review.
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DOI：
10.1186/s12943-015-0474-2
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发表时间：
2015-12-11
期刊：
影响因子：
37.3
通讯作者：
Hassa PO
中科院分区：
文献类型：
--
作者：
Camicia R;Winkler HC;Hassa PO
弥漫性大B细胞淋巴瘤（DLBCL）是一种临床异质性淋巴系统恶性肿瘤，是成人非霍奇金淋巴瘤中最常见的亚型，在世界上大多数发达地区死亡率最高。超过一半的DLBLC患者可以用标准R-CHOP方案治愈，但是由于治疗选择有限，大约30 - 40%的患者将发展为复发性/难治性疾病，这仍然是发病和死亡的主要原因。基因表达谱的最新进展已导致DLBCL的至少三种不同分子亚型的鉴定：生发中心B细胞样亚型、活化B细胞样亚型和原发性纵隔B细胞淋巴瘤亚型。此外，最近的研究结果不仅增加了我们对化疗耐药性分子基础的理解，而且还有助于确定DLBCL的分子亚群和药物干预的合理靶点，这可能允许亚型/亚群特异性分子靶向精准药物和个性化组合来预防和治疗复发性/难治性DLBCL。新的药物，如来那度胺，伊曲替尼，硼替佐米，CC-122，依帕珠单抗或匹鲁珠单抗作为单药或与（利妥昔单抗为基础的）化疗组合使用，已经证明了有希望的活性复发性/难治性DLBCL患者。最近已经鉴定了几种新的潜在药物靶点，例如BET溴结构域蛋白（BRD）-4、磷酸核糖焦磷酸合成酶（PRPS）-2、含大结构域的单ADP核糖基转移酶（ARTD）-9（也称为PARP 9）、deltex-3样E3泛素连接酶（DTX 3L）（也称为BBAP）、NF-κ B诱导激酶（NIK）和转化生长因子β受体（TGFβR）。本文综述了对复发性/难治性DLBCL分子基础的新认识，并总结了复发性/难治性DLBCL最有前途的药物靶点和实验性治疗，包括使用新药物，如来那度胺，伊曲替尼，硼替佐米，匹罗珠单抗，依帕珠单抗，brentuximab-vedotin或CAR T细胞，双重抑制剂，以及基于机制的组合实验性治疗。我们还提供了一个全面的和更新的列表，目前的药物，药物靶点和临床前和临床实验研究DLBCL。特别关注STAT 1，ARTD 9，DTX 3L和ARTD 8（也称为PARP 14）作为DLBCL不同分子亚群中的新型潜在药物靶点。本文的在线版本（doi：10.1186/s12943-015-0474-2）包含补充材料，可供授权用户使用。
Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin’s lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options. Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. Moreover, recent findings have not only increased our understanding of the molecular basis of chemotherapy resistance but have also helped identify molecular subsets of DLBCL and rational targets for drug interventions that may allow for subtype/subset-specific molecularly targeted precision medicine and personalized combinations to both prevent and treat relapsed/refractory DLBCL. Novel agents such as lenalidomide, ibrutinib, bortezomib, CC-122, epratuzumab or pidilizumab used as single-agent or in combination with (rituximab-based) chemotherapy have already demonstrated promising activity in patients with relapsed/refractory DLBCL. Several novel potential drug targets have been recently identified such as the BET bromodomain protein (BRD)-4, phosphoribosyl-pyrophosphate synthetase (PRPS)-2, macrodomain-containing mono-ADP-ribosyltransferase (ARTD)-9 (also known as PARP9), deltex-3-like E3 ubiquitin ligase (DTX3L) (also known as BBAP), NF-kappaB inducing kinase (NIK) and transforming growth factor beta receptor (TGFβR). This review highlights the new insights into the molecular basis of relapsed/refractory DLBCL and summarizes the most promising drug targets and experimental treatments for relapsed/refractory DLBCL, including the use of novel agents such as lenalidomide, ibrutinib, bortezomib, pidilizumab, epratuzumab, brentuximab-vedotin or CAR T cells, dual inhibitors, as well as mechanism-based combinatorial experimental therapies. We also provide a comprehensive and updated list of current drugs, drug targets and preclinical and clinical experimental studies in DLBCL. A special focus is given on STAT1, ARTD9, DTX3L and ARTD8 (also known as PARP14) as novel potential drug targets in distinct molecular subsets of DLBCL. The online version of this article (doi:10.1186/s12943-015-0474-2) contains supplementary material, which is available to authorized users.