PDF(Pubmed)
Abstract：
Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.
摘要：
2型神经纤维瘤病（NF2）相关神经鞘瘤病是一种遗传性疾病，可导致多种类型的神经系统肿瘤的发展。原发性和诊断性肿瘤类型是双侧前庭神经鞘瘤。NF2没有治愈或药物治疗。推荐的治疗方法包括手术切除和放疗，这两种情况都会使患者出现严重的神经功能缺损或增加未来恶性肿瘤的风险。我们先前的先导高通量药物筛选的结果基于小鼠merlin缺陷雪旺氏细胞（MD-SC）的生存力丧失，将磷酸肌醇3-激酶（PI3K）抑制剂鉴定为强候选物。在这里，我们使用新型人类神经鞘瘤模型细胞进行组合药物筛选。我们确定了一种I类PI3K抑制剂，pictilisib和p21活化激酶（PAK）抑制剂，由于在细胞活力测定中的高协同作用,PF-3758309作为顶部组合。在原位同种异体移植小鼠模型中,单一和组合疗法均显著降低小鼠MD-SC的生长。抑制剂组合促进小鼠merlin缺陷型施万（MD-SC）细胞中的细胞周期停滞和凋亡，并促进人MD-SC中的细胞周期停滞。这项研究确定了PI3K和PAK途径作为NF2相关神经鞘瘤病联合药物治疗的潜在靶标。
