Novel Drugs for Children With Cancer /Neurofibromatosis

治疗儿童癌症/神经纤维瘤病的新药

• 批准号: 6558756
• 负责人: Brigitte Widemann
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6558756
• 关键词: antimetabolites; antineoplastics; carboxypeptidase; clinical research; clinical trial phase I; drug adverse effect; drug design /synthesis /production; drug discovery /isolation; drug metabolism; drug screening /evaluation; enzyme inhibitors; guanosinetriphosphatase activating protein; human subject; human therapy evaluation; leukemia; magnetic resonance imaging; methotrexate; methotrexate analog; neoplasm /cancer chemotherapy; neurofibromatosis; neurofibromatosis type 1 protein /gene; pathologic process; pediatric neoplasm /cancer; pediatric pharmacology; pharmacokinetics

Summary: Anti-cancer drug discovery and development is moving towards a more rational and targeted approach based on our current understanding of the molecular pathogenesis of a variety of human cancers. The application of these new molecularly targeted agents to the treatment of childhood cancers is a focus of this project. The ras family of G-proteins play an important role in the transduction of signals that trigger cell proliferation, and mutations in ras genes are found in 30% of all human cancers. Ras proteins undergo post-translational farnesylation, which is required for activity of wild-type and mutant ras proteins, and this step can be inhibited by farnesyltransferase inhibitors, such as R115777. Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, with no standard treatment options, other than surgery available. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins. Decreased levels of neurofibromin have been shown to be associated with a constituitively activated ras-GTP status. The evaluation of R115777 in children with refractory solid tumors and neurofibromatosis type I (NF1) is therefore a rational choice. A phase I trial of R115777 for children with these tumors was recently completed, and based on the results of this phase I trial, a multi-institutional, randomized, double-blinded, placebo-controlled, cross-over phase II trial of R115777 for patients with NF1 and progressive plexiform neurofibromas was developed and is open for patient accrual. The endpoint of this trial will be time to disease progression. Volumetric MRI analysis will be used to evaluate disease progression. In addition, based on a 30% response rate to R115777 in adults with refractory leukemias, we developed a phase I trial of R115777 for children with refractory leukemias, which is also open for accrual. A series of pharmacodynamic studies evaluating the effect of R115777 are included in the NF1 and leukemia trials. The clinical development of antimetabolites, such as raltitrexed, and agents that modualte the effects of antimetabolites, such as the recombinant bacterial enzyme, carboxypeptidase-G2 (CPDG2), is also being studied. CPDG2 hydrolyzes methotexate (MTX) to inactive metabolites. We have extensively evaluated the use of CPDG2 as a rescue agent for patients with high-dose MTX (HDMTX) induced renal dysfunction. CPDG2 provides an alternative route of elimination for MTX and plasma MTX concentrations decline by >95% within minutes in all patients. We have studied the pharmacokinetics of 2,4-diamino-N10-methylpteroic acid (DAMPA), the product of MTX hydrolysis by CPDG2. Three DAMPA metabolites have been identified and account for the more rapid elimination of DAMPA compared to MTX in patients who receive CPDG2 for HDMTX-induced renal dysfunction. A New Drug Application for the use of CPDG2 in HDMTX induced renal dysfunction will be filed based on these data. We are also evaluating the potential benefit of intrathecal (IT) CPDG2 administration to patients who receive accidental IT MTX overdoses. To date three patients with ALL who had received accidental IT MTX overdoses from 190 mg to 600 mg were entered on this multi-institution protocol. All three patients tolerated IT CPDG2 administration well, experienced a dramatic decrease in cerebrospinal fluid MTX concentrations, and completely recovered from MTX-associated toxicities.

摘要：基于我们目前对多种人类癌症分子发病机制的了解，抗癌药物的发现和开发正在朝着更加合理和有针对性的方向发展。这些新的分子靶向药物在儿童癌症治疗中的应用是该项目的重点。 G 蛋白的 ras 家族在触发细胞增殖的信号转导中发挥着重要作用，30% 的人类癌症中都发现了 ras 基因的突变。 Ras 蛋白经历翻译后法尼基化，这是野生型和突变型 ras 蛋白活性所必需的，并且该步骤可以被法尼基转移酶抑制剂（例如 R115777）抑制。 1 型神经纤维瘤病 (NF1) 患者患中枢和周围神经系统肿瘤的风险增加，除了手术外，没有标准的治疗选择。神经纤维蛋白是 NF1 基因的产物，包含与 ras GTP 酶激活蛋白具有显着同源性的结构域。神经纤维蛋白水平降低已被证明与 ras-GTP 持续激活状态相关。因此，对患有难治性实体瘤和 I 型神经纤维瘤病 (NF1) 的儿童进行 R115777 的评估是一个合理的选择。 R115777针对患有这些肿瘤的儿童的I期试验最近完成，并且基于该I期试验的结果，针对R115777的多机构、随机、双盲、安慰剂对照、交叉II期试验患有 NF1 和进行性丛状神经纤维瘤的患者已开发出来，可供患者招募。该试验的终点将是疾病进展的时间。体积 MRI 分析将用于评估疾病进展。此外，基于 R115777 在成人难治性白血病患者中的缓解率为 30%，我们针对儿童难治性白血病开展了 R115777 的 I 期试验，该试验也开放进行累积。 NF1 和白血病试验中包含了一系列评估 R115777 效果的药效学研究。 抗代谢药（如雷替曲塞）和调节抗代谢药作用的药物（如重组细菌酶、羧肽酶-G2 (CPDG2)）的临床开发也在研究中。 CPDG2 将甲氨蝶呤 (MTX) 水解为无活性的代谢物。我们广泛评估了 CPDG2 作为高剂量 MTX (HDMTX) 引起的肾功能障碍患者的救援药物的用途。 CPDG2 提供了 MTX 的替代消除途径，所有患者的血浆 MTX 浓度在几分钟内下降了 > 95%。我们研究了 CPDG2 水解 MTX 的产物 2,4-二氨基-N10-甲基蝶酸 (DAMPA) 的药代动力学。已鉴定出三种 DAMPA 代谢物，并解释了在因 HDMTX 诱导的肾功能障碍而接受 CPDG2 治疗的患者中，与 MTX 相比，DAMPA 的消除更快。将根据这些数据提交使用 CPDG2 治疗 HDMTX 诱导的肾功能障碍的新药申请。我们还在评估鞘内 (IT) CPDG2 给药对意外服用 IT MTX 过量的患者的潜在益处。迄今为止，三名意外服用 MTX 过量（190 毫克至 600 毫克）的 ALL 患者参与了这一多机构方案。所有三名患者均能很好地耐受 IT CPDG2 给药，脑脊液 MTX 浓度显着下降，并完全从 MTX 相关毒性中恢复。