A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma.
A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma.
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DOI：
10.1038/s41420-021-00505-0
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发表时间：
2021-05-28
影响因子：
7
通讯作者：
Fairlie WD
中科院分区：
文献类型：
--
作者：
Arulananda S;O'Brien M;Evangelista M;Jenkins LJ;Poh AR;Walkiewicz M;Leong T;Mariadason JM;Cebon J;Balachander SB;Cidado JR;Lee EF;John T;Fairlie WD
恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，治疗仅限于顺铂和培美曲塞化疗。最近，我们发现靶向bcl -2调控的凋亡通路的药物可以在体外杀死MPM细胞系，并在体内控制肿瘤生长。这些研究表明，BCL-XL是主要的促生存BCL-2家族成员，其在细胞和患者肿瘤样本中的高表达相关。在这项研究中，我们发现了另一种靶向BCL-XL（和BCL-2）的抑制剂AZD4320，也可以在体外有效地杀死MPM肿瘤细胞（EC50值在200 nM范围内），并且通过使用AZD5991共同抑制MCL-1可以增强这种效果。此外，我们发现一种新型纳米颗粒AZD0466，其中AZD4320与聚乙二醇化的聚赖氨酸树状大分子化学偶联，在抑制小鼠异种移植研究中的肿瘤生长方面与标准化疗顺铂一样有效，并且当两种药物联合使用时，这种效果会增强。关键的是，与其他靶向BCL-XL的bh3模拟物相比，在整个治疗期间，与BCL-XL抑制相关的靶毒性——血小板减少的程度显著降低。这些临床前研究结果为未来对MPM以及其他依赖BCL-XL的实体肿瘤类型的新型bh3模拟制剂的临床评估提供了依据。
Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.
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DOI：
10.1056/nejmoa1513257
发表时间：
2016-01-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Roberts AW;Davids MS;Pagel JM;Kahl BS;Puvvada SD;Gerecitano JF;Kipps TJ;Anderson MA;Brown JR;Gressick L;Wong S;Dunbar M;Zhu M;Desai MB;Cerri E;Heitner Enschede S;Humerickhouse RA;Wierda WG;Seymour JF
通讯作者：
Seymour JF
影响因子：
20.4
作者：
Tsao, Anne S.;Lindwasser, O. Wolf;Malik, Shakun M.
通讯作者：
Malik, Shakun M.
影响因子：
158.5
作者：
Seymour, J. F.;Kipps, T. J.;Kater, A. P.
通讯作者：
Kater, A. P.
影响因子：
28.2
作者：
Lok, Sheau W.;Whittle, James R.;Lindeman, Geoffrey J.
通讯作者：
Lindeman, Geoffrey J.
影响因子：
17.1
作者：
Leverson, Joel D.;Phillips, Darren C.;Souers, Andrew J.
通讯作者：
Souers, Andrew J.