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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。神经纤维瘤病1（NF 1）是一种常见的常染色体显性遗传性进行性遗传病，发病率为1：3000（在美国有> 80，000人受影响）。NF 1的特点是多样的，渐进的皮肤，神经，骨骼和肿瘤的表现，没有标准的药物治疗方案。NF 1患者发生中枢和外周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%）、恶性外周神经鞘瘤（5%）和神经纤维肉瘤（6%）。丛状神经纤维瘤是一种神经鞘肿瘤，它沿着神经生长并累及神经的多个分支。它们是发病率的主要来源，导致毁容、神经功能受损，并且在某些情况下发展为恶性外周神经鞘肿瘤。神经纤维蛋白，NF-1基因产物，含有一个与ras GTP酶激活蛋白（GAP）具有显著同源性的结构域。ras蛋白在细胞信号传导途径中是不可或缺的，并且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。NF 1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NF 1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，其中法尼基异戊二烯基团通过酶法尼基蛋白转移酶（FPT酶）添加到许多细胞蛋白质中。G蛋白的ras家族是被FPTase修饰的蛋白质类别之一。H-、K-和N-ras是21 kDa鸟嘌呤核苷酸结合蛋白，其控制多种细胞信号传导事件。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。NF 1患者没有生殖系ras突变。然而，从NF 1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型激活的ras-GTP状态。神经纤维蛋白是NF 1基因的产物，含有一个与ras GTP酶激活蛋白（GAP）具有显著同源性的结构域。在这些细胞系中，存在正常水平的GAP，但神经纤维蛋白水平降低，支持NF 1基因作为肿瘤抑制基因的作用。ras癌蛋白功能的研究进展为抗肿瘤干预提供了新的思路。Ras作为胞质前体合成，其在一系列翻译后修饰后最终定位于质膜的胞质面。这一系列翻译后修饰的第一个必要步骤是添加法呢基部分。这种修饰对于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适当生化靶标，从而预防ras介导的细胞转化。R115777是一种有效的和选择性的非肽模拟物抑制剂的FPTase在体外和体内。在几项临床前研究中，R115777显示出抑制H-ras、K-ras和N-ras转化肿瘤的生长。还对在我们的儿科I期试验中接受治疗的30名儿童（中位年龄13岁，年龄范围5至17岁）的血浆样本进行了口服R115777的药代动力学分析。一般而言，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.