Department of Physical Chemistry, Vinca Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.
Department of Hematology, Clinical Hospital Centre Zemun, Vukova 9, 11000 Belgrade, Serbia.
Int J Mol Sci. 2024 Oct 23;25(21):11384. doi: 10.3390/ijms252111384.
Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies and T-cell engagers, and immune checkpoint inhibitors. Candidate drugs explored in ongoing clinical trials are coupled with diverse toxicity issues and refractoriness to drugs. According to the literature on DLBCL, the promise for new therapeutic targets lies in epigenetic alterations, B-cell receptor and NF-κB pathways. Herein, we present putative targets hiding in lipid pathways, ferroptosis, and the gut microbiome that could be used in addition to immuno-chemotherapy to improve the general health status of DLBCL patients, thus increasing the chance of being cured. It may be time to devote more effort to exploring DLBCL metabolism to discover novel druggable targets. We also performed a bibliometric and knowledge-map analysis of the literature on DLBCL published from 2014-2023.
弥漫性大 B 细胞淋巴瘤 (DLBCL) 是一种具有巨大生物学和临床异质性的恶性肿瘤。基于转录组或基因组方法，多年来已经发展出几种不同的分类方案，将 DLBCL 细分为具有临床（预后）相关性的亚群，但每种方案都有未分类的样本。本文概述了 DLBCL 肿瘤生物学背后的实际和潜在药物靶点，并探讨了其（潜在）用途所带来的挑战和缺点。讨论了治疗方式，包括小分子抑制剂、裸抗体、抗体药物偶联物、嵌合抗原受体、双特异性抗体和 T 细胞衔接器、以及免疫检查点抑制剂。正在进行的临床试验中探索的候选药物与多种毒性问题和对药物的耐药性有关。根据关于 DLBCL 的文献，新的治疗靶点的前景在于表观遗传学改变、B 细胞受体和 NF-κB 途径。本文提出了隐藏在脂质途径、铁死亡和肠道微生物组中的假定靶点，这些靶点可以与免疫化疗一起使用，以改善 DLBCL 患者的整体健康状况，从而增加治愈的机会。也许是时候投入更多精力探索 DLBCL 的代谢，以发现新的可成药靶点了。我们还对 2014-2023 年发表的关于 DLBCL 的文献进行了文献计量和知识图谱分析。
