North American Juvenile Myelomonocytic Leukemia Project

描述(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，该途径中的RAS和NF1基因被发现异常。这种失调导致JMML细胞在体外对GM-CSF表现出选择性超敏。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。NCI的CTEP分部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学小组实施，是第二阶段窗口/第三阶段试验。将在II期窗口测试法尼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。这种试验设计的许多优点之一是，它允许对未经治疗但未产生耐药性的JMML患者进行单一药物疗效的严格评估。如果一个第二阶段的试剂落后，该方案被设计为允许替代不同的试剂，而不会中断研究的其余部分。在第三阶段试验过程中，三种实验试剂几乎可以完全测试。实验室研究将评估它们是否真正起到了基于机制的疗法的作用。这项应用的主要目的是利用该方案中的患者资源作为积累病例的渠道，以解决几项关键的临床和基础科学研究，包括：1)测试Famesyl Transfer ase抑制剂Rl15777在未经治疗的JMML患者中的有效性；2)利用这一II期窗口方法评估其他针对JMML的分子靶向、基于机制的疗法；以及3)确定JMML患者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记物相关联，以确定是否存在治疗上真正相关的、生物定义的JMML亚集，未来可以针对这些基于机制的治疗进行专门指导。因此，本申请中提出的转译实验是基于我们对JMML发病机制的理解，并将提供关于靶向治疗的药效学的新数据。除了JMML，这些研究可能会发现抑制RAS的药物，这些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.