Targeting SYK Kinase in AML

在 AML 中靶向 SYK 激酶

• 批准号: 10220876
• 负责人: Kimberly Stegmaier
• 金额: $ 2.05万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220876
• 关键词: 3-Dimensional; Acute Myelocytic Leukemia; B cell differentiation; Biological Assay; Biological Markers; Biology; Bone Marrow; Cell Line; Cells; Chemicals; Clinic; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Dependence; Diagnosis; Disease; Drug Combinations; Enrollment; Enzymes; Event; FLT3 gene; Flow Cytometry; Gene Expression Profile; Generations; Genes; Genetic; Genomic approach; Goals; Hematopoietic; Immunohistochemistry; In Vitro; Left; Malignant Neoplasms; Measures; Minority; Modeling; Molecular; Molecular Abnormality; Myeloproliferative disease; Open Reading Frames; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase I/II Clinical Trial; Phase II Clinical Trials; Phosphotransferases; Pre-Clinical Model; Protein Tyrosine Kinase; Relapse; Resistance; Role; SYK gene; Sampling; Signal Transduction; Signal Transduction Pathway; Testing; Translating; Translations; Tyrosine Kinase Inhibitor; Vertebral column; Work; acute myeloid leukemia cell; base; biomarker identification; candidate marker; chemotherapy; drug testing; experimental study; functional genomics; genetic approach; genetic signature; improved; in vivo; interest; leukemia; mouse model; new therapeutic target; next generation sequencing; novel drug combination; peripheral blood; predicting response; resistance mechanism; response; response biomarker; targeted agent; targeted treatment; therapeutic target

Project Summary/Abstract New targeted therapies are urgently needed for acute myeloid leukemia (AML), where little progress has been made in improving long-term patient survival despite significant inroads into understanding the molecular pathogenesis of this disease. We previously discovered spleen tyrosine kinase (SYK) as a new target in AML, with FLT3-ITD a biomarker of response to SYK inhibitors in AML cells. These findings become immediately translatable as numerous SYK inhibitors are entering clinical trials for patients with cancer, including AML. The translation of SYK inhibitors to the clinic for patients with AML is the focus of this project. In Aim 1 of this proposal, we will study SYK activation in AML cell lines and patient blasts to determine whether SYK activation promotes resistance to current AML therapy. In this Aim, we will also determine whether SYK inhibitors synergize with drugs currently used to treat patients with AML, both in vitro and in vivo, to inform second- generation SYK inhibitor clinical trials. In Aim 2, we will test specific hypotheses and conduct unbiased functional genomic studies to identify resistance mechanisms to SYK inhibitors in AML. We expect that these experiments will inform new drug combinations for testing with SYK inhibitors. Aim 3 will focus on performing the correlative biology studies for two Phase I/II clinical trials testing SYK inhibitors in patients with AML. In this Aim, we will use next-generation sequencing of panels of leukemia-associated genes, immunohistochemistry and intracellular phospho-specific flow cytometry to measure activated SYK, BH3 profiling, and gene expression signature assays to identify biomarkers of response to SYK inhibitors and to confirm target inhibition using AML samples from patients treated on the clinical trial. At the completion of this study, we expect to confirm on-target, anti-leukemia activity of a SYK inhibitor in patients with AML and to inform second- generation clinical trials through the identification of drug combinations with SYK inhibitors and through the identification of biomarkers of response in patients with AML treated with a SYK inhibitory drug.

项目摘要/摘要 急性需要新的靶向疗法来急性髓细胞性白血病（AML），那里的进展很少 尽管大量了解分子 这种疾病的发病机理。我们以前在AML中发现脾脏酪氨酸激酶（SYK）是一个新目标， 使用FLT3-ITD对AML细胞中SYK抑制剂的反应生物标志物。这些发现立即变成 可以翻译为许多SYK抑制剂正在接受包括AML在内的癌症患者的临床试验。这 该项目的重点是将SYK抑制剂转换为AML患者的诊所。在目标1中 提案，我们将研究AML细胞系和患者爆炸中的SYK激活，以确定SYK是否激活 促进对当前AML治疗的抵抗力。在此目标中，我们还将确定SYK抑制剂是否 与目前用于治疗AML患者的药物协同作用，包括体外和体内，以告知第二次 生成SYK抑制剂临床试验。在AIM 2中，我们将检验特定的假设并进行公正 功能基因组研究以鉴定AML中SYK抑制剂的抗性机制。我们希望这些 实验将为新药组合提供用于使用SYK抑制剂测试的新药组合。 AIM 3将专注于执行 针对AML患者的两种I/II临床试验测试SYK抑制剂的相关生物学研究。在这个 目的，我们将使用与白血病相关基因的下一代测序，免疫组织化学 和细胞内磷酸特异性流式细胞仪，以测量活化的SYK，BH3分析和基因 表达签名测定法以识别对SYK抑制剂反应的生物标志物并确认靶标 使用临床试验治疗的患者的AML样品抑制作用。在完成这项研究时，我们 期望确认AML患者中SYK抑制剂的靶标的抗白血病活性 通过鉴定与SYK抑制剂的药物组合以及通过 用SYK抑制性药物治疗的AML患者的反应生物标志物的鉴定。