Clinical development of drugs for children with cancer &

摘要：基于我们目前对各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加理性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本项目的重点。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30%的人类癌症中发现了ras基因突变。Ras蛋白经过翻译后的法尼基化，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）抑制。1型神经纤维瘤病（NF1）患者发生中枢和周围神经系统肿瘤的风险增加，除了手术之外没有标准的治疗选择。神经纤维蛋白是NF1基因的产物，含有一个与ras gtpase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性激活的ras-GTP状态有关。因此，R115777在顽固性实体瘤和I型神经纤维瘤病（NF1）患儿中的评价是一种合理的选择。R115777用于这些肿瘤儿童的I期试验已经完成，基于该I期试验的结果，一项多机构、随机、双盲、安慰剂对照、交叉的R115777用于NF1和进行性丛状神经纤维瘤患者的II期试验已经开展，并开放患者累积。这项试验的终点是疾病进展的时间。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患者中的30%应答率，我们开发了R115777用于儿童难治性白血病患者的I期试验，该试验刚刚完成累积。一系列评估R115777效果的药效学研究包括在NF1和白血病试验中。R115777的II期临床试验针对患有急性髓性白血病的儿童和年轻人，目前正在准备第二次完全细胞形态缓解。该试验的终点将是评估R115777对微小残留疾病的影响。其他目前处于早期临床试验或临床开发阶段的新药包括艾替隆B类似物和微管蛋白结合剂BMS-247550，治疗难治性癌症的raf激酶和受体酪氨酸激酶抑制剂BAY 43-9006，以及治疗NF1的抗纤维化药物吡非尼酮。吡非尼酮I期临床试验已完成，吡非尼酮治疗NF1和进行性丛状神经纤维瘤儿童的II期临床试验刚刚开始。此外，将进行一项多机构试验，用标准药物进行新辅助化疗，用于治疗儿童肉瘤，以评估有无NF1患者的恶性周围神经鞘肿瘤（MPNSTs）的反应率。抗代谢物的临床开发，如雷替曲塞，以及调节抗代谢物作用的药物，如重组细菌酶，羧肽酶- g2 (CPDG2)，也正在研究中。CPDG2将甲氨蝶呤（MTX）水解为无活性代谢物。我们已经广泛评估了CPDG2作为高剂量MTX （HDMTX）诱导肾功能障碍患者的拯救剂的使用。CPDG2提供了另一种消除MTX的途径，在所有患者中，血浆MTX浓度在几分钟内下降了100 - 95%。我们研究了CPDG2水解MTX的产物- 2,4-二氨基- n10 -甲基翼鸟酸（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CPDG2治疗hdmtx诱导肾功能障碍的患者中，与MTX相比，DAMPA的消除速度更快。基于这些数据，CPDG2用于HDMTX诱导肾功能障碍的新药申请将提交。我们也在评估鞘内（IT） CPDG2给药对意外接受IT MTX过量的患者的潜在益处。迄今为止，7名意外过量服用MTX的患者（从155毫克到600毫克）接受了IT CPDG2。所有患者对IT CPDG2耐受良好，脑脊液MTX浓度显著下降，MTX相关毒性完全恢复，只有2例患者出现轻度记忆受损。

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 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 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 just completed accrual. A series of pharmacodynamic studies evaluating the effect of R115777 are included in the NF1 and leukemia trials. A phase II trial of R115777 is for children and young adults with AML and second complete cytomorphological remission is now in preparation. The endpoint of this trial will be to evaluate the effects of R115777 on minimal residual disease. 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 pirfenidone completed accrual, and a phase II trial of pirfenidone for children with NF1 and progressive plexiform neurofibromas just opened for accrual. 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 methotrexate (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.