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.

项目概要/摘要 急性髓系白血病 (AML) 迫切需要新的靶向治疗，但目前该领域的进展甚微 尽管在了解分子机制方面取得了重大进展，但仍致力于改善患者的长期生存 本病的发病机制。我们之前发现脾酪氨酸激酶 (SYK) 作为 AML 的新靶点， FLT3-ITD 是 AML 细胞中对 SYK 抑制剂反应的生物标志物。这些发现立即成为 这意味着许多 SYK 抑制剂正在进入针对癌症患者（包括 AML）的临床试验。这 将 SYK 抑制剂转化为针对 AML 患者的临床是该项目的重点。在这个目标1中 建议，我们将研究 AML 细胞系和患者原始细胞中的 SYK 激活，以确定 SYK 激活是否 促进对当前 AML 治疗的耐药性。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（体外和体内）协同作用，以告知第二 一代SYK抑制剂临床试验。在目标 2 中，我们将测试具体假设并进行公正的 功能基因组研究以确定 AML 中 SYK 抑制剂的耐药机制。我们期望这些 实验将为 SYK 抑制剂测试的新药物组合提供信息。目标 3 将侧重于表现 两项 I/II 期临床试验的相关生物学研究，在 AML 患者中测试 SYK 抑制剂。在这个 目标，我们将使用白血病相关基因组的下一代测序、免疫组织化学 和细胞内磷酸特异性流式细胞术来测量激活的 SYK、BH3 分析和基因 表达特征测定，以识别对 SYK 抑制剂反应的生物标志物并确认靶标 使用临床试验中治疗的患者的 AML 样本进行抑制。在完成这项研究后，我们 期望确认 SYK 抑制剂在 AML 患者中的靶向抗白血病活性，并通知后续研究 通过鉴定与 SYK 抑制剂的药物组合并通过 鉴定接受 SYK 抑制药物治疗的 AML 患者反应的生物标志物。