North American Juvenile Myelomonocytic Leukemia Project

描述（由申请人提供）： JMML的发病机制与通过Ras途径的GM-CSF生长因子信号转导失调有关，在该途径中的RAS和NF 1基因中发现异常。 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的新治疗方式之一，13-顺式维甲酸治疗，似乎可以调节这种GM-CSF超敏反应。一种新的JMML多模态治疗方案最近已被NCI的CTEP分支批准。 本方案将通过儿童肿瘤组实施，是一项II期窗口期/III期试验。将在II期窗口期测试法呢基转移酶抑制剂的实验性治疗，然后在III期部分测试13-顺式维甲酸、化疗和干细胞移植。 这种类型的试验设计的许多优点之一是，它允许在未经治疗的JMML患者中严格评估单一药物的疗效，这些患者尚未产生耐药性。 如果一种II期药物尾部，该方案的设计允许替换不同的药物，而不会中断研究的其余部分。 在III期试验过程中，可以对三种实验药物进行几乎完全的测试。 实验室研究将评估它们是否真正作为基于机制的治疗剂。 本申请的主要目的是利用本方案的患者资源作为累积病例的渠道，以解决几项关键临床和基础科学研究，包括：1）测试法呢基转移酶抑制剂R115777在未经治疗的JMML患者中的功效，2）利用该II期窗口方法来评估用于JMML的其他分子靶向的、基于机制的治疗剂，和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，未来基于机制的治疗可以具体针对这些亚群。 因此，本申请中提出的转化实验是基于我们对JMML发病机制的理解，并将提供有关靶向治疗药物药效学的新数据。除了JMML之外，这些研究可能会发现抑制Ras的药物，最终证明这些药物广泛适用于其他骨髓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.