North American Juvenile Myelomonocytic Leukemia Project

北美幼年粒单核细胞白血病项目

• 批准号: 6580974
• 负责人: PETER D. EMANUEL
• 金额: $ 31.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-03 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580974
• 关键词: SDS polyacrylamide gel electrophoresis; adolescence (12-20); alkyltransferase; cancer registry /resource; cell bank /registry; clinical research; clinical trial phase II; clinical trial phase III; drug screening /evaluation; enzyme inhibitors; enzyme therapy; gene interaction; gene mutation; human subject; human therapy evaluation; immunoprecipitation; myelogenous leukemia; neoplasm /cancer chemotherapy; pathologic process; patient oriented research; pediatric neoplasm /cancer; polymerase chain reaction; single strand conformation polymorphism; statistics /biometry; terminal nick end labeling; western blottings

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.

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，该途径中的 RAS 和 NF1 基因存在异常。 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-顺式视黄酸疗法，似乎可以调节这种 GM-CSF 超敏反应。一种新的 JMML 多模式治疗方案最近已获得 NCI CTEP 分支的批准。 该方案将通过儿童肿瘤学组实施，是一项 II 期窗口/III 期试验。法尼基转移酶抑制剂的实验性治疗将在 II 期窗口进行测试，随后在 III 期部分进行 13-顺式视黄酸、化疗和干细胞移植。 此类试验设计的众多优点之一是，它允许在未治疗且未产生耐药性的 JMML 患者中严格评估单一药物的疗效。 如果一种 II 期药物出现尾随，该方案的设计允许在不中断研究其余部分的情况下更换不同的药物。 在 III 期试验过程中，三种实验药物几乎可以得到全面测试。 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。 此应用程序的主要目的是利用此协议中的患者资源作为累积病例的渠道，以解决几个关键的临床和基础科学研究，包括：1) 测试法尼基转移酶抑制剂 Rl15777 在未经治疗的 JMML 患者中的疗效，2) 利用这一 II 期窗口方法来评估 JMML 的其他分子靶向、基于机制的治疗方法，以及 3) 确定 JMML 患者中 NFI 和 RAS 基因异常的实际频率，以及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 子集，未来基于机制的治疗可以专门针对这些子集。 因此，本申请中提出的转化实验基于我们对 JMML 发病机制的理解，并将提供有关靶向治疗药效学的新数据。除了 JMML 之外，这些研究可能会发现抑制 Ras 的药物，最终证明它们广泛适用于其他骨髓恶性肿瘤和广泛的人类癌症。