治疗 1 型神经纤维瘤病相关恶性周围神经鞘瘤的新模型系统和靶向治疗的开发,Genes

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治疗 1 型神经纤维瘤病相关恶性周围神经鞘瘤的新模型系统和靶向治疗的开发
Genes ( IF 2.8 ) Pub Date : 2020-04-28 , DOI: 10.3390/genes11050477
Kyle B Williams _{1,

2} , David A Largaespada _{1,

2}

Affiliation

1 型神经纤维瘤病 (NF1) 是一种常见的遗传性疾病和癌症易感综合征（出生比例为 1:3000），由抑癌基因 NF1 突变引起。NF1 编码神经纤维蛋白，Ras 信号通路的负调节因子。患有 NF1 的个体经常会出现源自施万细胞谱系的良性周围神经系统肿瘤（神经纤维瘤），其中一些进一步发展为恶性周围神经鞘瘤（MPNST）。神经纤维瘤和 MPNST 的治疗选择极其有限，主要依赖于手术切除和细胞毒性化疗。确定良性神经纤维瘤和 MPNST 的新治疗靶点对于改善患者的治疗结果和生活质量至关重要。最近在 NF1 患者中进行的使用丝裂原激活蛋白激酶 (MEK) 抑制剂治疗有症状的丛状神经纤维瘤的临床试验显示出非常有希望的结果。然而，MEK 抑制剂并非对所有患者都有效，并且具有显着的副作用。此外，初步证据表明单药使用 MEK 抑制剂进行 MPNST 治疗将会失败。在这里，我们描述了导致 MEK 抑制剂被鉴定为治疗 NF1 相关肿瘤的有希望的疗法的临床前工作，以及它们在治疗 MPNST 方面缺乏单药疗效的可能原因。此外，我们描述了寻找 MEK 以外的治疗 MPNST 靶点的工作。这些研究来自 RAS 生物化学、体外药物筛选、施万细胞肿瘤的正向遗传筛选以及具有致癌 RAS 基因突变的细胞的合成致死筛选的研究。最后，我们讨论了利用 CRISPR/Cas9 技术在人类施万细胞中利用 NF1 功能丧失突变进行药物筛选和合成致死的新方法。

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New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

更新日期：2020-04-28

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