Clinical Research Support

项目摘要 临床研究支持核心3致力于两项主要工作。首先，我们负责获得 在诊断和复发时以及 辅助研究的临床试验中的特定时间点。诊断和复发样本用于执行 四个项目中的每一个。因此，可以测定人白血病原始细胞经历白血病细胞周期的能力。 在项目1中描述了响应于各种试剂的细胞凋亡，包括标准和 动态的在项目2中，将评估CBL在白血病发生中的重要性; 艾伯特实验室将阐明如何下游通路激活这种突变可能代表治疗目标。 项目3研究SALL 4 B在白血病中的作用。阿姆斯特朗/费舍尔实验室（项目4）正在研究 MLL重排白血病中与白血病发生机制相关的转录因子生物学。我们 预期menin抑制剂与来那度胺和/或维奈托克组合将具有治疗效果， 潜力临床研究支持核心3将从处于不同阶段的患者中获取样本， 已签署01-206同意书的疾病患者，该同意书允许样本库。我们将获得这些样本 并将它们转移到生物标本核心1，供项目中的科学家注释和使用。第二 核心3的主要目标是执行来自赠款中描述的科学的临床试验。我们 预计在赠款资助期间将进行三项主要的临床试验。在第二年和第三年，我们预计我们将 进行一项致力于确认动态BH 3谱的试验将允许选择特定的激酶 抑制剂与维奈托克联合治疗晚期复发性/难治性AML患者。 我们计划进一步比较激酶抑制剂加维奈托克治疗的患者与 用“标准”维奈托克加低甲基化药物治疗。项目2将导致临床试验， 维奈托克与达沙替尼联合，能够抑制在细胞中活化的林恩/SRC通路， CBL突变。初步数据表明，menin联合来那度胺和/或维奈托克 可能在MLL重排白血病中具有协同作用-这将导致临床试验接近资金结束 期临床试验设计，包括辅助样本的时间和处理，以确认目标 参与，将在生物统计核心2的协助下获得信息。生物统计核心2还将协助 这些临床试验的分析和发表。希望通过收集精心注释的 用于项目内相关分析的样本将导致对白血病生物学的更深入理解， 或许还能找到更多可以利用的目标临床试验有望改善结果 白血病患者的情况。

Project Summary The Clinical Research Support Core 3 is dedicated to two major efforts. First, we are responsible for obtaining human samples from patients with myeloid malignancies at the time of diagnosis and relapse as well as at specific timepoints in clinical trials for ancillary studies. The diagnostic and relapse samples are used to perform research in each of the four projects. Thus, human leukemic blasts can be assayed for their ability to undergo apoptosis in response to various agents are described in Project 1 including BH3 profiling, both standard and dynamic. In Project 2 the importance of CBL in leukemogenesis will be assessed; the studies conducted in the Ebert lab will elucidate how downstream pathways activated by this mutation may represent therapeutic targets. Project 3 investigates the role of SALL4B in leukemia. The Armstrong/Fisher labs (Project 4) are investigating transcription factor biology relevant to mechanism of leukemogenesis in MLL rearranged leukemia. We anticipate that menin inhibition in combination with either lenalidomide and/or venetoclax will have therapeutic potential. Clinical Research Support Core 3 will be obtaining samples from patients at various stages of their disease who have signed consent for 01-206 which allows for sample banking. We will obtain these samples and transfer them to Biospecimen Core 1 for annotation and availability for scientists in the projects. The second major goal of the Core 3 is to perform clinical trials emanating from science described in the grants. We anticipated three major clinical trials during the grant funding period. In years 2 and 3, we expect that we will be performing a trial dedicated to confirming the dynamic BH3 profiling will allow selection of specific kinase inhibitors to be combined with venetoclax in the treatment of patients with advanced relapsed/refractory AML. We plan to further compare the outcome of patients treated with a kinase inhibitor plus venetoclax with those treated with “standard” venetoclax plus hypomethylated agent. Project 2 will lead to a clinical trial involving venetoclax in combination with dasatinib, capable of inhibiting the LYN/SRC pathway activated in cells with a CBL mutation. Preliminary data suggests that menin in combination with either lenalidomide and/or venetoclax may be synergistic in MLL rearranged leukemia-which will lead to a clinical trial toward the end of the funding period. The clinical trial designs including the timing and processing of ancillary samples to confirm target engagement, will be informed with the assistance of Biostatistical Core 2. Biostatistical Core 2 will also assist in the analysis and publication of these clinical trials. It is hoped that through collection of carefully annotated samples for use in relevant assays within the projects will lead to a greater understanding of leukemia biology, and perhaps lead to additional targets that can be exploited. The clinical trials will hopefully improve the outcome of patients with leukemia.