■NF2相关脑膜瘤是进行性的,高度病态,对化疗无反应,强调需要改进的治疗方法。我们已经在NF2缺陷型肿瘤中建立了雷帕霉素(mTOR)信号机制靶标的异常激活,导致第一代和第二代mTOR抑制剂的临床试验。然而,结果喜忧参半,显示稳定的肿瘤生长,没有因不良副作用而引起的收缩。为了解决这些限制,在这里,我们探索了第三代的潜力,使用临床前工具化合物RMC-6272的双构mTOR复合物1(mTORC1)抑制剂。
■使用人类NF2缺陷型脑膜瘤细胞系,我们比较了mTOR抑制剂雷帕霉素(第一代),INK128(第二代),和RMC-6272(第三代)使用体外剂量反应测试,细胞周期分析,和免疫印迹。此外,在NF2-null3D球形脑膜瘤模型中评估RMC-6272的疗效,并在2个原位脑膜瘤小鼠模型中评估了其体内潜力。
■治疗脑膜瘤细胞显示,不像雷帕霉素,RMC-6272表现出优异的生长抑制作用,细胞周期停滞,和完全抑制磷酸化4E-BP1(mTORC1读出)。此外,RMC-6272具有比INK128更长的保留时间,并且在蛋白质水平上抑制几种eIF4E敏感靶标的表达。NF2球状体的RMC-6272处理显示出显著的尺寸收缩以及减少的增殖。此外,小鼠体内研究显示,与载体对照相比,RMC-6272可有效阻断脑膜瘤的生长。
■我们在NF2临床前模型中的研究支持了未来可能的第三代临床评估,研究性mTORC1抑制剂,如RMC-5552,作为NF2的潜在治疗策略。
UNASSIGNED: NF2-associated meningiomas are progressive, highly morbid, and nonresponsive to chemotherapies, highlighting the need for improved treatments. We have established aberrant activation of the mechanistic target of rapamycin (mTOR) signaling in NF2-deficient tumors, leading to clinical trials with first- and second-generation mTOR inhibitors. However, results have been mixed, showing stabilized tumor growth without shrinkage offset by adverse side effects. To address these limitations, here we explored the potential of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors using the preclinical tool compound RMC-6272.
UNASSIGNED: Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, the efficacy of RMC-6272 was assessed in NF2-null 3D-spheroid meningioma models, and its in vivo potential was evaluated in 2 orthotopic meningioma mouse models.
UNASSIGNED: Treatment of meningioma cells revealed that, unlike rapamycin, RMC-6272 demonstrated superior growth inhibitory effects, cell-cycle arrest, and complete inhibition of phosphorylated 4E-BP1 (mTORC1 readout). Moreover, RMC-6272 had a longer retention time than INK128 and inhibited the expression of several eIF4E-sensitive targets on the protein level. RMC-6272 treatment of NF2 spheroids showed significant shrinkage in size as well as reduced proliferation. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls.
UNASSIGNED: Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.