AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma
AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma
复制标题
DOI：
10.1158/0008-5472.can-06-0284
复制
发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
--
作者：
Sathornsumetee, Sith;Hjelmeland, Anita B.;Rich, Jeremy N.
恶性神经胶质瘤是对常规疗法具有抗性的高度增殖性和血管生成性癌症。虽然RAS和RAF突变在胶质瘤中不常见，但RAS活性在胶质瘤中增加。此外，血管内皮生长因子及其同源受体在胶质瘤中高度表达。我们现在报告，AAL 881，一种新的低分子量的激酶活性抑制剂与B-RAF，C-RAF（RAF-1），和VEGF受体-2（VEGFR 2），显示对神经胶质瘤细胞系和异种移植物的活性。在培养中，AAL 881以浓度依赖性方式抑制RAF的下游效应子，抑制与G相关的增殖、细胞周期停滞、诱导凋亡和减少集落形成。AAL 881可抑制牛主动脉内皮细胞增殖，抑制肿瘤细胞分泌血管内皮生长因子，并通过人工细胞外基质抑制胶质瘤细胞的侵袭。口服给药的AAL 881在非荷瘤小鼠中耐受良好，体重减轻最小。建立s.c.在用口服AAL 881的10天疗程治疗的免疫受损小鼠中生长的人恶性神经胶质瘤异种移植物相对于对照肿瘤表现出生长延迟，经常导致长期完全消退。与安慰剂对照相比，AAL 881治疗延长了携带原位神经胶质瘤异种移植物的免疫受损小鼠的存活。与蛛网膜下腔成分相比，原位AAL 881治疗的肿瘤的实质内部分发生了与血管破裂一致的广泛坏死。这些作用与我们先前使用VEGFR 2抑制剂的经验不同，表明靶向RAF本身或与VEGFR 2组合诱导神经胶质瘤中的显著肿瘤反应，并可作为恶性神经胶质瘤患者的新治疗方法。
Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G, cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.