Spriano Filippo, Aresu Luca, Cascione Luciano, Risi Giorgia, Arribas Alberto J, Napoli Sara, Forster-Gross Nicole, Bachmann Felix, Engelhardt Marc, Lane Heidi, Bertoni Francesco
Institute of Oncology Research, Faculty of Biomedical Sciences, USI Bellinzona, Switzerland.
Department of Veterinary Science, University of Turin Grugliasco, Turin, Italy.
Am J Cancer Res. 2023 May 15;13(5):2076-2086. eCollection 2023.
Microtubules are major components of the cellular cytoskeleton, ubiquitously founded in all eukaryotic cells. They are involved in mitosis, cell motility, intracellular protein and organelle transport, and maintenance of cytoskeletal shape. Avanbulin (BAL27862) is a microtubule-targeted agent (MTA) that promotes tumor cell death by destabilization of microtubules. Due to its unique binding to the colchicine site of tubulin, differently from other MTAs, avanbulin has previously shown activity in solid tumor cell lines. Its prodrug, lisavanbulin (BAL101553), has shown early signs of clinical activity, especially in tumors with high EB1 expression. Here, we assessed the preclinical anti-tumor activity of avanbulin in diffuse large B cell lymphoma (DLBCL) and the pattern of expression of EB1 in DLBCL cell lines and clinical specimens. Avanbulin showed a potent anti-lymphoma activity, which was mainly cytotoxic with potent and rapid apoptosis induction. Median IC50 was around 10 nM in both ABC and GCB-DLBCL. Half of the cell lines tested showed an induction of apoptosis already in the first 24 h of treatment, the other half in the first 48 h. EB1 showed expression in DLBCL clinical specimens, opening the possibility for a cohort of patients that could potentially benefit from treatment with lisavanbulin. These data show the basis for further preclinical and clinical evaluation of lisavanbulin in the lymphoma field.
微管是细胞骨架的主要组成部分，普遍存在于所有真核细胞中。它们参与有丝分裂、细胞运动、细胞内蛋白质和细胞器运输以及细胞骨架形状的维持。阿凡布林（BAL27862）是一种微管靶向药物（MTA），通过使微管不稳定来促进肿瘤细胞死亡。与其他MTA不同，由于其与微管蛋白的秋水仙碱位点独特结合，阿凡布林此前已在实体瘤细胞系中显示出活性。其前药利沙凡布林（BAL101553）已显示出临床活性的早期迹象，尤其是在EB1高表达的肿瘤中。在此，我们评估了阿凡布林在弥漫性大B细胞淋巴瘤（DLBCL）中的临床前抗肿瘤活性以及EB1在DLBCL细胞系和临床标本中的表达模式。阿凡布林显示出强大的抗淋巴瘤活性，主要具有细胞毒性，并能有效且快速地诱导凋亡。在ABC和GCB-DLBCL中，半数抑制浓度（IC50）中位数均约为10 nM。半数受试细胞系在治疗的最初24小时内即显示出凋亡诱导，另一半则在最初48小时内显示。EB1在DLBCL临床标本中表达，这为可能从利沙凡布林治疗中获益的一批患者带来了希望。这些数据为利沙凡布林在淋巴瘤领域的进一步临床前和临床评估奠定了基础。
