Targeted Therapy of Lyn in Myelodysplastic Syndrome

Lyn 治疗骨髓增生异常综合征的靶向治疗

• 批准号: 7680896
• 负责人: Seth Joel Corey
• 金额: $ 27.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680896
• 关键词: Abnormal Granulocyte; Acute Myelocytic Leukemia; Address; Adult; Affect; Allogenic; Apoptosis; Appearance; Behavior; Biological Markers; Biological Models; Biological Response Modifiers; Birth; Blood Cells; Cell Line; Cells; Child; Childhood; Class; Colony-Stimulating Factor Receptors; Development; Disease; Distal; Dose; Drug Delivery Systems; Dysmyelopoietic Syndromes; Event; Evolution; Frequencies; Functional disorder; Genetic; Genetic Polymorphism; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Growth; Hematopoiesis; Hypercellular Bone Marrow; Individual; Infection; Laboratories; Lesion; Life; Malignant - descriptor; Modeling; Monosomy 7; Mutate; Myelogenous; Myeloid Cells; Myelopoiesis; Neutropenia; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Protein Isoforms; Protein Tyrosine Kinase; Receptor Signaling; Resistance; Risk; Signal Pathway; Signal Transduction; Staging; Stem cell transplant; Syndrome; Testing; Tissues; Tyrosine Kinase Inhibitor; base; cytopenia; inhibitor/antagonist; insight; mouse model; novel therapeutics; older patient; prevent; receptor; restoration; small molecule; src-Family Kinases

DESCRIPTION (provided by applicant): Myelodysplastic Syndromes (MDS) are a disorder, increasing in frequency, for which there is poor understanding of its pathophysiology and no curative therapy short of an allogeneic stem cell transplant. Since most patients are elderly, new therapeutic strategies are desperately needed. MDS evolves from dysregulated clonal hematopoiesis to acute myeloid leukemia (AML). In early MDS, there is accelerated apoptosis of blood cells in a hypercellular bone marrow. In late MDS, apoptosis is deficient and a block in differentiation occurs. Our laboratory has been studying signaling pathways in cells stimulated by Granulocyte Colony-Stimulating Factor (G-CSF). Abnormal G-CSF Receptor signaling is found in several forms of pediatric and adult MDS: 1) children with severe congenital neutropenia have a 10,000-fold increase risk of developing MDS/AML - almost all of whom express a truncated G-CSF Receptor; 2) expression of the differentiation-defective G-CSF Receptor isoform is elevated in AML, MDS, and monosomy 7 patients; 3) a functional polymorphism affecting the distal, domain of the G-CSF Receptor occurs in MDS patients. Therefore, we hypothesize that disordered myelopoiesis due to dysfunctional G-CSF Receptor signaling underlies some cases of MDS and that targeted therapy may successfully delay or prevent leukemic transformation. We have identified the Src kinase Lyn as a major effector of G-CSF Receptor signaling. Chiefly limited to blood cells, Lyn provides a feasible drug target. To address these hypotheses, we propose the following specific aims: 1) Characterize the Lyn-dependent growth controlling pathways driven by the distal domain of the G-CSF Receptor and determine their presence in primary MDS cells; 2) Characterize the signaling changes due to increased expression of Class IV G-CSF Receptor and its presence in primary MDS cells; and 3) Test the effect of Lyn targeted therapy in mouse model and cell lines. These studies will provide rationale for a phase II study using Src inhibitors for subsets of MDS patients.

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一种发病率不断增加的疾病，对其病理生理学的了解很少，除了异基因干细胞移植外没有治愈性治疗。由于大多数患者是老年人，迫切需要新的治疗策略。MDS从失调的克隆造血发展为急性髓性白血病（AML）。在早期MDS中，在细胞过多的骨髓中存在血细胞的加速凋亡。在晚期MDS中，细胞凋亡是缺乏的，并且发生分化阻滞。我们的实验室一直在研究由粒细胞集落刺激因子（G-CSF）刺激的细胞中的信号通路。在几种形式的儿科和成人MDS中发现异常的G-CSF受体信号传导：1）患有严重先天性中性粒细胞减少症的儿童具有10，000倍增加的发展MDS/AML的风险-几乎所有这些儿童都表达截短的G-CSF受体; 2）分化缺陷型G-CSF受体同种型的表达在AML、MDS和单体7患者中升高; 3）MDS患者中存在影响G-CSF受体远端结构域的功能多态性。因此，我们假设，由于G-CSF受体信号传导功能障碍导致的骨髓生成障碍是某些MDS病例的基础，靶向治疗可能成功延迟或预防白血病转化。我们已经确定Src激酶林恩是G-CSF受体信号传导的主要效应子。林恩的作用仅限于血细胞，因此提供了一个可行的药物靶点。为了解决这些假设，我们提出了以下具体目标：1）表征由G-CSF受体的远端结构域驱动的Lyn-dependent生长控制途径，并确定它们在原代MDS细胞中的存在; 2）表征由于IV类G-CSF受体的表达增加及其在原代MDS细胞中的存在引起的信号传导变化; 3）在小鼠模型和细胞系中检测林恩靶向治疗的效果。这些研究将为使用Src抑制剂治疗MDS患者亚组的II期研究提供依据。