Clinical development of novel drugs for children with ca

摘要：基于我们目前对多种人类癌症分子发病机制的认识，抗癌药物的发现和开发正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这个项目的一个重点。Ras家族的G蛋白在触发细胞增殖的信号转导中起着重要作用，在所有人类癌症中发现了30%的ras基因突变。RAS蛋白经历翻译后的法尼化，这是野生型和突变型ras蛋白活性所必需的，这一步骤可以被法尼基转移酶抑制剂，如R115777所抑制。1型神经纤维瘤病(NF1)患者发生中枢和外周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，它含有一个与ras GTP酶激活蛋白有显著同源性的结构域。神经纤维蛋白水平的降低已被证明与ras-GTP的结构性激活状态有关。因此，评估R115777在儿童难治性实体瘤和I型神经纤维瘤病(NF1)中的应用是一个合理的选择。R115777针对这些肿瘤的儿童患者的I期试验最近已经完成，根据这一I期试验的结果，针对NF1和进行性丛状神经纤维瘤患者的R115777的多机构、随机、双盲、安慰剂对照的交叉II期试验已经开发出来，并向患者开放。这项试验的终点将是疾病进展的时间。自动容量磁共振分析用于评估疾病进展。此外，基于成人难治性白血病对R115777的30%应答率，我们开发了一项针对儿童难治性白血病的R115777的I期试验，该试验也是开放的。NF1和白血病试验中包括了一系列评估R115777效果的药效学研究。其他目前处于早期临床试验或临床开发中的新药包括Epothilone B类似物和微管蛋白结合剂BMS-247550，用于难治性癌症的RAF激酶和受体酪氨酸激酶抑制剂BAY 43-9006，以及用于NF1的抗纤维化药物吡非尼酮。吡诺酮的第一阶段试验接近完成，第二阶段试验正在开发中。此外，还将进行一项使用标准药物治疗儿童肉瘤的新辅助化疗的多机构试验，以评估患有和不患有NF1的患者对恶性周围神经鞘瘤(MPNST)的有效率。 抗代谢药物的临床发展，如雷替曲塞，以及拮抗抗代谢药物的药物，如重组细菌酶，羧基肽酶-G2(CPDG2)，也在研究中。CPDG2将甲氧西林(MTX)水解为非活性代谢物。我们广泛评估了CPDG2作为大剂量甲氨蝶呤(HDMTX)所致肾功能不全患者的救援剂的使用。CPDG2为MTX提供了另一种消除途径，所有患者的血浆MTX浓度在几分钟内下降了95%。本文研究了CPDG2对甲氨蝶呤(MTX)的水解产物2，4-二氨基-N10-甲基蝶酸(DAMPA)的药代动力学。已经确定了三种DAMPA代谢物，与MTX相比，在接受CPDG2治疗HDMTX引起的肾功能障碍的患者中，DAMPA的消除更快。基于这些数据，将提出CPDG2用于治疗HDMTX引起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过量患者的潜在益处。到目前为止，有7名患者意外接受了从155毫克到600毫克的IT MTX过量治疗，他们接受了IT CPDG2。所有患者对IT CPDG2的耐受性良好，脑脊液MTX浓度显著降低，除2名患者记忆轻度受损外，MTX相关毒性完全恢复。

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 is time to disease progression. Automated volumetric MRI analysis is 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. Other new agents that are currently in early clinical trials or clinical development include the epothilone B analog and tubulin binding agent BMS-247550, and the raf kinase and receptor tyrosine kinase inhibitor BAY 43-9006 for refractory cancers, and the antifibrotic agent, pirfenidone for NF1. A phase I trial of pirenidone is close to completion, and a phase II trial is in development. In addition, a multi-institutional trial of neoadjuvant chemotherapy with standard agents used to treat pediatric sarcomas will be performed to assess the response rate of malignant peripheral nerve sheath tumors (MPNSTs) in patients with and without NF1. 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 seven patients who had received accidental IT MTX overdoses from 155 mg to 600 mg received IT CPDG2. All patients tolerated IT CPDG2 administration well, experienced a dramatic decrease in cerebrospinal fluid MTX concentrations, and completely recovered from MTX-associated toxicities with exception of mild impaired memory in 2 patients.