North American Juvenile Myelomonocytic Leukemia Project

描述（由申请人提供）：JMML的发病机制与通过Ras途径介导的GM-CSF生长因子信号转导失调有关，在该途径中发现Ras和NF1基因异常。这种失调导致JMML细胞在体外表现出对GM-CSF的选择性超敏反应。JMML的一种新治疗方式，13-顺式维甲酸治疗，似乎可以调节这种GM-CSF超敏反应。NCI CTEP分支最近批准了一种新的JMML多模式治疗方案。该方案将通过儿童肿瘤组实施，是一项II期窗口/ III期试验。在II期窗口期，将测试一种法尼基转移酶抑制剂的实验性治疗，然后在III期进行13-顺式维甲酸、化疗和干细胞移植。这种类型的试验设计的众多优点之一是，它允许严格评估单一药物对未发生耐药性的未经治疗的JMML患者的疗效。如果一种II期药物失效，该方案的设计允许用不同的药物替代，而不会破坏研究的其余部分。在III期试验过程中，三种实验药物几乎可以完全测试。实验室研究将评估它们是否真正起到基于机制的治疗作用。该应用程序的主要目的是利用本协议中的患者资源作为积累病例的渠道，以解决几个关键的临床和基础科学研究，包括：1)测试famesyl转移酶抑制剂Rl15777在未治疗的JMML患者中的疗效，2)利用这种II期窗口方法评估其他分子靶向的、基于机制的JMML治疗方法，3)确定JMML患者中NFI和RAS基因异常的实际频率，并将这些结果与已知的临床预后标志物相关联，以确定是否存在治疗相关的、生物学定义的JMML亚群。未来以机制为基础的治疗方法可以被专门指导。因此，本申请中提出的翻译实验是基于我们对JMML发病机制的理解，并将为靶向治疗的药效学提供新的数据。除了JMML，这些研究可能会发现抑制Ras的药物，最终被证明广泛适用于其他髓系恶性肿瘤和广泛的人类癌症。

DESCRIPTION (provided by applicant): The pathogenesis of JMML has been linked to dysregulated GM-CSF growth factor signal transduction through the Ras pathway, with abnormalities identified in the RAS and NF1 genes in this pathway. This dysregulation results in JMML cells demonstrating selective hypersensitivity to GM-CSF in vitro. One of the new treatment modalities in JMML, 13-cis retinoic acid therapy, appears to modulate this GM-CSF hypersensitivity. A new multi-modality treatment protocol for JMML has recently been approved by the CTEP branch of the NCI. This protocol will be administered through the Children's Oncology Group and is a phase II window/phase III trial. Experimental therapy with a farnesyl transferase inhibitor will be tested in the phase II window, followed by 13-cis retinoic acid, chemotherapy, and stem cell transplantation in the phase III portion. One of the many advantages of this type of trial design is that it permits the rigorous evaluation of the efficacy of a single agent in untreated JMML patients who have not developed drug resistance. If one phase II agent tails, the protocol is designed to allow for the substitution of a different agent without disrupting the rest of the study. Three experimental agents can be nearly fully tested during the course of the phase III trial. Laboratory studies will evaluate whether they are truly acting as mechanism-based therapeutics. The principal aims of this application are to utilize the patient resources from this protocol as a conduit for accruing cases to address several key clinical and basic science investigations including: 1) to test the efficacy of the famesyl transferase inhibitor, Rl15777, in untreated JMML patients, 2) to utilize this phase II window approach to evaluate other molecularly targeted, mechanism-based therapeutics for JMML, and 3) to determine the actual frequency of NFI and RAS gene abnormalities in JMML patients and correlate these results with known clinical prognostic markers to determine if therapeutically relevant, biologically-defined subsets of JMML exist, towards which future mechanism-based therapies can be specifically directed. Thus, the translational experiments proposed in this application are based on our understanding of JMML pathogenesis, and will provide novel data about the pharmacodynamics of targeted therapeutics. Beyond JMML, these studies may uncover agents that inhibit Ras that ultimately prove to be broadly applicable to other myeloid malignancies and to a broad range of human cancers.