A PHASE II RANDOMIZED, CROSS-OVER, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL O

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。1型神经纤维瘤病（NF1）是一种常见的常染色体显性进行性遗传病，在美国发病率为1:3000（约80000人患病）。NF1的特点是多样的、进行性的皮肤、神经、骨骼和肿瘤表现，没有标准的药物治疗选择。NF1患者发生中枢和周围神经系统肿瘤的风险增加，包括丛状神经纤维瘤（27%）、视神经胶质瘤（15-20%）、嗜铬细胞瘤（1%）、恶性周围神经鞘肿瘤（5%）和神经纤维肉瘤（6%）。丛状神经纤维瘤是沿神经长度生长的神经鞘肿瘤，累及神经的多个分支。它们是发病率的主要来源，引起毁容，神经功能损害，在某些情况下发展为恶性周围神经鞘肿瘤。神经纤维蛋白是NF1基因产物，含有一个与ras gtpase激活蛋白（GAP）具有显著同源性的结构域。ras蛋白是细胞信号通路中不可或缺的一部分，ras的激活导致细胞增殖。gap催化ras- gtp （ras的活性形式）水解为ras- gdp并导致ras失活。NF1患者的神经纤维蛋白水平降低，这与激活的ras-GTP状态有关。因此，针对抑制ras的药物是NF1和进行性丛状神经纤维瘤患者潜在治疗药物试验的合理选择。法尼基化是一种翻译后修饰，通过法尼基-蛋白质转移酶（FPTase）将一个法尼基异戊二烯基团添加到许多细胞蛋白上。G蛋白的ras家族是被FPTase修饰的一类蛋白。H-， K-和N-ras是21 kDa的鸟嘌呤核苷酸结合蛋白，控制多种细胞信号转导事件。突变的ras基因具有将细胞转化为恶性表型的能力，并且在大约30%的人类癌症中观察到ras突变。NF1患者没有种系ras突变。然而，从NF1患者的恶性神经鞘瘤建立的肿瘤细胞系已被证明具有组成性激活的ras-GTP状态。神经纤维蛋白是NF1基因的产物，含有一个与ras gtpase激活蛋白（GAP）具有显著同源性的结构域。在这些细胞系中，GAP水平正常，但神经纤维蛋白水平降低，支持NF1基因作为肿瘤抑制基因的作用。对ras癌蛋白功能的认识的进展为抗肿瘤干预提供了新的切入点。Ras作为细胞质前体合成，经过一系列翻译后修饰，最终定位于质膜的细胞质表面。这一系列翻译后修饰的第一步是添加一个法尼基片段。这种修改对于ras功能是必不可少的。FPTase似乎是开发ras翻译后加工抑制剂的合适生化靶标，从而防止ras介导的细胞转化。R115777是一种有效的、选择性的非拟肽性FPTase抑制剂，在体内和体外都是如此。在一些临床前研究中，R115777被证明可以抑制H-ras、K-ras和N-ras转化肿瘤的生长。口服R115777的药代动力学分析也已在30名儿童（中位年龄13岁，年龄范围5至17岁）的血浆样本中进行，这些儿童接受了我们的儿科I期试验。一般来说，R1157777在成人和儿童中的药代动力学相似。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neurofibromatosis 1 (NF1) is a common autosomal dominant, progressive genetic disorder with an incidence of 1:3000 (>80,000 persons affected in The United States). NF1 is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic manifestations with no standard drug treatment options available. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas (27%) optic gliomas gliomas (15-20%), pheochromocytomas (1%), malignant peripheral nerve sheath tumors (5%), and neurofibrosarcomas (6%). Plexiform neurofibromas are nerve sheath tumors that grow along the length of nerves and involve multiple branches of a nerve. They are a major source of morbidity, causing disfigurement, impairment of nerve function, and in some cases development of malignant peripheral nerve sheath tumors. Neurofibromin, the NF1 gene product, contains a domain with significant homology to ras GTPase-activating proteins (GAP). The ras proteins are integral in cell signaling pathways, and activation of ras leads to cell proliferation. GAPs catalyze the hydrolysis of ras-GTP (the active form of ras) to ras-GDP and lead to ras inactivation. Patients with NF1 have decreased levels of neurofibromin, which is associated with an activated ras-GTP status. Agents directed at inhibiting ras, therefore, are a rational choice for trials of potential therapeutic agents in patients with NF1 and progressive plexiform neurofibromas. Farnesylation is a post-translational modification in which a farnesyl isoprene group is added to a number of cellular proteins by the enzyme, farnesyl-protein transferase (FPTase). The ras family of G proteins is one of the classes of proteins that are modified by FPTase. H-, K-, and N-ras are 21 kDa guanine nucleotide-binding proteins that control a multitude of cell signaling events. Mutant ras genes have the ability to transform cells into a malignant phenotype, and ras mutations have been observed in approximately 30% of all human cancers. Patients with NF1 do not have germline ras mutations. However, tumor cell lines established from malignant schwannomas of NF1 patients have been shown to have a constituitively activated ras-GTP status. Neurofibromin, which is the product of the NF1 gene, contains a domain that shows significant homology to ras GTPase-activating proteins (GAP). In these cell lines, there are normal levels of GAP, but decreased levels of neurofibromin, supporting the role of the NF1 gene as a tumor suppressor gene. Advances in the understanding of ras oncoprotein function suggest novel points for anti-tumor intervention. Ras is synthesized as a cytosolic precursor that ultimately localizes to the cytoplasmic face of the plasma membrane after a series of post-translational modifications. The first obligatory step in this series of post- translational modifications is the addition of a farnesyl moiety. This modification is essential for ras function. FPTase appears to be an appropriate biochemical target for the development of inhibitors of post-translational processing of ras resulting in prevention of ras-mediated cellular transformation. R115777 is a potent and selective non-peptidomimetic inhibitor of FPTase both in vitro and in vivo. In several preclinical studies, R115777 was shown to inhibit the growth of H-ras, K-ras and N-ras transformed tumors. Pharmacokinetic analysis of oral R115777 has also been performed on plasma samples from 30 children (median age 13 years, age range 5 to 17 years) treated on our pediatric phase I trial. In general the pharmacokinetics of R1157777 are similar in adults and children.