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.

项目总结/摘要 急性髓细胞白血病（AML）迫切需要新的靶向治疗，目前进展甚微。 尽管在理解分子生物学方面取得了重大进展， 本病的发病机制。我们之前发现脾酪氨酸激酶（SYK）是AML的一个新靶点， FLT 3-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 许多SYK抑制剂正在进入癌症患者（包括AML）的临床试验。的 将SYK抑制剂用于AML患者的临床治疗是该项目的重点。目标1 我们将研究AML细胞系和患者原始细胞中的SYK活化，以确定SYK活化是否 促进对当前AML疗法的耐药性。在这个目标中，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- 一代SYK抑制剂临床试验。在目标2中，我们将测试特定的假设，并进行无偏 功能基因组研究，以确定AML中SYK抑制剂的耐药机制。我们预计这些 实验将告知新的药物组合与SYK抑制剂的测试。目标3将专注于执行 两项在AML患者中测试SYK抑制剂的I/II期临床试验的相关生物学研究。在这 目的是，我们将使用下一代白血病相关基因组测序，免疫组化， 和细胞内磷酸特异性流式细胞术来测量活化的SYK、BH 3谱和基因表达。 表达特征测定，以鉴定对SYK抑制剂的应答的生物标志物，并确认靶向 使用来自在临床试验中治疗的患者的AML样品进行抑制。在本研究结束时，我们 预计将确认SYK抑制剂在AML患者中的靶向抗白血病活性，并告知第二批- 通过鉴定与SYK抑制剂的药物组合，并通过 鉴定用SYK抑制药物治疗的AML患者中的应答生物标志物。