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，我们有责任获得 诊断和复发时的髓系恶性肿瘤患者的人类样本 用于辅助研究的临床试验的具体时间点。诊断和复发样本用于执行 在四个项目中的每一个项目中进行研究。因此，可以检测人类白血病原始细胞的能力。 在项目1中描述了对各种药物的响应的细胞凋亡，包括BH3图谱，包括标准的和 活力四射。在项目2中，将评估CBL在白血病发生中的重要性；在 埃伯特实验室将阐明这种突变激活的下游通路如何代表治疗靶点。 项目3研究SALL4B在白血病中的作用。阿姆斯特朗/费舍尔实验室(项目4)正在调查 MLL重排白血病发生机制的转录因子生物学研究我们 预期薄荷素抑制与来那度胺和/或万乃馨联合使用将具有治疗作用 潜力。临床研究支持核心3将从患者的不同阶段获取样本 已经签署了01-206同意书的疾病患者，允许样本银行。我们会拿到这些样品 并将它们转移到Biospecimen Core 1进行注释，供项目中的科学家使用。第二 CORE 3的主要目标是进行由拨款中描述的科学产生的临床试验。我们 预计在赠款资助期内进行三项主要临床试验。在第二年和第三年，我们预计我们将 进行一项专门用于确认动态BH3图谱的试验将允许选择特定的激酶 抑制剂联合万乃馨治疗晚期复发/难治性急性髓细胞白血病。 我们计划进一步比较使用激酶抑制剂加万乃馨的患者的结果。 用“标准”万乃馨加去甲基化剂治疗。项目2将导致一项临床试验，涉及 文奈德与达沙替尼联合应用可抑制白血病细胞Lyn/SRC通路的激活 CBL突变。初步数据显示，薄荷宁与来那度胺和/或万乃馨联合使用 可能对MLL重排白血病有协同作用-这将导致临床试验接近资金结束 句号。临床试验设计包括辅助样本的计时和处理以确定靶点 参与，将在生物统计核心2的协助下通知。生物统计核心2还将协助 对这些临床试验的分析和发表。希望通过收集经过仔细注释的 用于项目内相关化验的样本将有助于更好地了解白血病生物学， 或许还会带来更多可以利用的目标。临床试验有望改善结果。 白血病患者的比例。

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.