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Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells.
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2020-04-01 , DOI: 10.1158/1078-0432.ccr-19-2202
Elizabeth A Lemm 1 , Beatriz Valle-Argos 1 , Lindsay D Smith 1 , Johanna Richter 1 , Yohannes Gebreselassie 1 , Matthew J Carter 2 , Jana Karolova 3, 4 , Michael Svaton 3, 4 , Karel Helman 5 , Nicola J Weston-Bell 1 , Laura Karydis 1 , Chris T Williamson 6 , Georg Lenz 7 , Jeremy Pettigrew 6 , Curtis Harwig 6 , Freda K Stevenson 1 , Mark Cragg 2 , Francesco Forconi 1 , Andrew J Steele 1 , Jennifer Cross 6 , Lloyd Mackenzie 6 , Pavel Klener 3, 4 , Graham Packham 1
Affiliation  

PURPOSE PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.

中文翻译:


新型 SHIP1 磷酸酶激活剂抑制恶性 B 细胞中 PI3K 信号传导的临床前评估。



目的 PI3K信号传导是B细胞肿瘤的共同特征,包括慢性淋巴细胞白血病(CLL)和弥漫性大B细胞淋巴瘤(DLBCL),PI3K抑制剂已被引入临床。然而,仍然明显需要开发针对 PI3K 信号传导的新策略。 PI3K 活性被包含 Src 同源结构域 2 的肌醇-5'-磷酸酶 1 (SHIP1) 所抵消,在这里,我们在 B 细胞恶性肿瘤的临床前模型中表征了一种新型 SHIP1 激活剂 AQX-435 的活性。实验设计使用原代CLL细胞和DLBCL衍生细胞系评估AQX-435的体外活性。使用 DLBCL 细胞系和患者来源的异种移植模型评估 AQX-435 单独或与布鲁顿氏酪氨酸激酶 (BTK) 抑制剂依鲁替尼组合的体内活性。结果 使用 AQX-435 对 SHIP1 进行药理学激活足以抑制抗 IgM 诱导的 PI3K 介导的信号传导,包括诱导 AKT 磷酸化和 MYC 表达,而不影响上游 SYK 磷酸化。 AQX-435还与BTK抑制剂依鲁替尼配合,增强对抗IgM诱导的AKT磷酸化的抑制。与正常 B 细胞相比,AQX-435 优先诱导 CLL 细胞的 caspase 依赖性凋亡,并克服了微环境刺激的体外存活促进作用。最后,AQX-435在体内降低AKT磷酸化和DLBCL生长,并与依鲁替尼配合抑制肿瘤生长。结论 我们使用 AQX-435 的结果表明,SHIP1 激活可能是单独或与依鲁替尼联合治疗 B 细胞肿瘤的一种有效的新型治疗策略。
更新日期:2020-04-01
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