Clinical Development of Novel Drugs for Children with Ca

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（包括丛状神经纤维瘤）的风险增加，除手术外没有标准治疗选择。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。一项针对难治性实体瘤或NF 1和无法手术的丛状神经纤维瘤儿童的R115777 I期试验已完成，基于该I期试验的结果，开发了一项针对NF 1和进行性丛状神经纤维瘤患者的R115777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，该试验完成了累积。NF 1和白血病试验中纳入了一系列评估R115777作用的药效学研究。R115777的II期试验是针对患有AML的儿童和年轻人，第二次完全细胞形态学缓解正在准备中。本试验的终点是评价R115777对无病生存期和微小残留病变的影响。目前处于早期临床试验或临床开发阶段的其他新药物包括埃坡霉素B类似物和微管蛋白结合剂BMS-247550（即将进入难治性实体瘤儿童的II期试验）、raf激酶和受体酪氨酸激酶抑制剂BAY 43-9006（用于难治性癌症和NF 1）以及抗纤维化药物吡非尼酮（用于NF 1）。一项吡非尼酮I期试验已完成招募，一项吡非尼酮治疗NF 1和进行性丛状神经纤维瘤儿童的II期试验目前正在招募。NF 1临床试验的发展正在扩大到包括NF 1成人临床试验的发展。将进行一项新辅助化疗的多机构试验，以评估高级别不可切除的散发性或NF 1相关恶性外周神经鞘瘤（MPNST）的缓解率。该试验通过美国国防部的临床试验奖获得资金，并将作为MPNST新型药物开发的平台。皮肤神经纤维瘤是NF 1的标志，虽然这些肿瘤不会发生恶性转化，但它们会导致NF 1的显著美容问题和发病率。通过与NHGRI的合作，正在开发一项研究NF 1成人皮肤神经纤维瘤和遗传修饰剂的自然史的试验，并通过Bench to Bedside Award获得资金。这项试验可能导致对NF 1和皮肤神经纤维瘤患者的治疗研究。

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, including plexiform neurofibromas, 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 refractory solid tumors or NF1 and inoperable plexiform neurofibromas 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 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 endpoints of this trial will be to evaluate the effects of R115777 on disease-free survival and 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, which will soon enter phase II testing in children with refractory solid tumors, the raf kinase and receptor tyrosine kinase inhibitor BAY 43-9006 for refractory cancers and NF1, 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 is currently open to accrual. The development of clinical trials for NF1 is being expanded to include the development of clinical trials for adults with NF1. A multi-institutional trial of neoadjuvant chemotherapy will be performed to assess the response rate of high grade unresectable sporadic or NF1 associated malignant peripheral nerve sheath tumors (MPNSTs). This trial receives funding through a Clinical Trial Award by the US Department of Defense, and will serve as a platform for the development of novel agents for MPNSTs. Dermal neurofibromas are the hallmark of NF1, and while these tumors do not undergo malignant transformation, they cause significant cosmetic problems and morbidity in NF1. Through collaboration with the NHGRI, a trial to study the natural history of dermal neurofibromas and genetic modifiers in adults with NF1 is in development and receives funding through a Bench to Bedside Award. This trial may lead to treatment studies for individuals with NF1 and dermal neurofibromas.