North American Juvenile Myelomonocytic Leukemia Project

北美幼年粒单核细胞白血病项目

• 批准号: 7263969
• 负责人: PETER D. EMANUEL
• 金额: $ 2.86万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263969
• 关键词: Address; Adolescent; American; Basic Science; Biochemical; Biological; Cancer Therapy Evaluation Program; Cells; Children' s Oncology Group; Clinical; Clinical Trials; Data; Disease; Drug resistance; Farnesyl Transferase Inhibitor; Frequencies; Future; Gene Abnormality; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; HRAS gene; Human; Hypersensitivity; In Vitro; Internet; Investigation; Investigational Therapies; Isotretinoin; Juvenile Myelomonocytic Leukemia; Laboratory Study; Link; Malignant Neoplasms; Modality; Myeloproliferative disease; NF1 gene; Pathogenesis; Pathway interactions; Patients; Pharmacodynamics; Phase; Phase III Clinical Trials; Prognostic Marker; Protein Farnesylation; Protocols documentation; Range; Research Personnel; Resources; Rest; Sampling; Signal Transduction; Site; Stem cell transplant; Supervision; System; Tail; Testing; Therapeutic; Tissue Banks; Toxic effect; Transferase; Treatment Protocols; base; cell registry; chemotherapy; design; efficacy evaluation; improved; in vivo; inhibitor/antagonist; leukemia; mouse model; novel; research study; response; therapeutic target; translational study

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的发病机理已与通过RAS途径失调的GM-CSF生长因子信号转导失调，在该途径中的RAS和NF1基因中鉴定出异常。 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 13-钙视黄酸治疗中的新治疗方式之一似乎调节了这种GM-CSF超敏反应。 NCI的CTEP分支最近批准了针对JMML的新的多模式治疗方案。 该方案将通过儿童肿瘤学组进行管理，是II期窗口/III期试验。将在II期窗口中测试使用Farnesyl转移酶抑制剂的实验疗法，然后在III期部分中进行13 cis视黄酸，化学疗法和干细胞移植。 这种类型的试验设计的众多优点之一是，它允许对单个药物在未患有耐药性的未经治疗的JMML患者中的疗效进行严格的评估。 如果一个II期代理的尾巴，则该方案旨在允许替换不同的药物，而不会破坏研究的其余部分。 在III期试验过程中，可以几乎对三种实验试剂进行全面测试。 实验室研究将评估它们是否真正充当基于机制的治疗学。 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 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记相关，以确定是否存在治疗性相关的JMML的治疗性相关，生物定义的子集存在，可以专门针对未来基于机制的疗法。 因此，本应用程序中提出的翻译实验是基于我们对JMML发病机理的理解，并将提供有关靶向治疗药物的药效学的新数据。除了JMML之外，这些研究可能会揭示抑制RA的药物，这些药物最终被证明广泛适用于其他髓样恶性肿瘤和广泛的人类癌症。