Clinical development of novel drugs for children with ca

总结：基于我们目前对多种人类癌症分子发病机制的理解，抗癌药物的发现和开发正朝着更合理和更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起重要作用，并且在所有人类癌症的30%中发现ras基因的突变。Ras蛋白进行翻译后法尼基化，这是野生型和突变型ras蛋白的活性所必需的，并且该步骤可以被法尼基转移酶抑制剂如R115777抑制。1型神经纤维瘤病（NF 1）患者发生中枢和外周神经系统肿瘤的风险增加，除手术外没有标准治疗方案。神经纤维蛋白是NF 1基因的产物，含有与ras GTP酶激活蛋白具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组成型激活的ras-GTP状态相关。因此，R115777在难治性实体瘤和I型神经纤维瘤病（NF 1）儿童中的评价是一个合理的选择。R115777治疗这些肿瘤儿童的I期试验最近完成，基于该I期试验的结果，开发了一项R115777治疗NF 1和进行性丛状神经纤维瘤患者的多机构、随机、双盲、安慰剂对照、交叉II期试验，并开放供患者招募。本试验的终点是至疾病进展的时间。自动体积MRI分析用于评估疾病进展。此外，基于R115777在成人难治性白血病中的30%应答率，我们开发了R115777用于儿童难治性白血病的I期试验，该试验也开放供招募。NF 1和白血病试验中纳入了一系列评价R115777作用的药效学研究。目前正在临床开发的用于难治性癌症和NF 1的其他新药包括埃博霉素B类似物和微管蛋白结合剂BMS-247550以及抗纤维化剂吡非尼酮。此外，将进行一项多机构的新辅助化疗试验，使用标准药物治疗小儿肉瘤，以评估有和无NF 1患者的恶性外周神经鞘瘤（MPNST）的缓解率。 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（CPDG 2））的临床开发也正在研究中。CPDG 2水解甲氨蝶呤（MTX）为无活性代谢物。我们已经广泛评估了CPDG 2作为高剂量MTX（HDMTX）诱导的肾功能不全患者的补救药物的用途。CPDG 2提供了MTX的替代消除途径，并且所有患者的血浆MTX浓度在几分钟内下降>95%。我们研究了甲氨蝶呤（MTX）被CPDG 2水解的产物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，并解释了在接受CPDG 2治疗HDMTX诱导的肾功能不全的患者中，与MTX相比，DAMPA的消除更快。将根据这些数据提交CPDG 2用于HDMTX诱导的肾功能不全的新药申请。我们还评估了鞘内（IT）CPDG 2给药对意外接受IT MTX过量的患者的潜在益处。迄今为止，三名意外IT MTX过量服用190 mg至600 mg的ALL患者已进入该多机构方案。所有三名患者耐受IT CPDG 2管理良好，经历了脑脊液MTX浓度急剧下降，并完全从MTX相关的毒性恢复。

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 clinical development for refractory cancers and NF1 include the epothilone B analog and tubulin binding agent BMS-247550 and the antifibrotic agent, pirfenidone. 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 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.