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: 7034786
• 负责人: Seth Joel Corey
• 金额: $ 26.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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/7034786
• 关键词: acute myelogenous leukemia; antineoplastics; apoptosis; biological signal transduction; biomarker; cell growth regulation; cell line; cell proliferation; clinical research; colony stimulating factor; drug screening /evaluation; dyserythropoietic anemia; gene mutation; growth factor receptors; hematopoiesis; human subject; human tissue; kinase inhibitor; laboratory mouse; neoplasm /cancer genetics; preneoplastic state; protein structure; protein tyrosine kinase; proteomics

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，对其病理生理学了解甚少，除了同种异体干细胞移植外没有其他治疗方法。由于大多数患者都是老年人，迫切需要新的治疗策略。 MDS 从克隆造血失调发展为急性髓系白血病 (AML)。在早期MDS中，细胞过多的骨髓中血细胞凋亡加速。在MDS晚期，细胞凋亡不足并且分化受阻。我们的实验室一直在研究粒细胞集落刺激因子 (G-CSF) 刺激的细胞中的信号传导通路。异常的 G-CSF 受体信号传导存在于多种形式的儿童和成人 MDS 中：1) 患有严重先天性中性粒细胞减少症的儿童患 MDS/AML 的风险增加 10,000 倍 - 几乎所有儿童都表达截短的 G-CSF 受体； 2) 分化缺陷型 G-CSF 受体亚型的表达在 AML、MDS 和单体 7 患者中升高； 3) MDS 患者中出现影响 G-CSF 受体远端结构域的功能多态性。因此，我们推测，由于 G-CSF 受体信号传导功能障碍导致的骨髓生成紊乱是某些 MDS 病例的基础，而靶向治疗可以成功地延迟或预防白血病转化。我们已经确定 Src 激酶 Lyn 是 G-CSF 受体信号传导的主要效应器。 Lyn 主要限于血细胞，提供了可行的药物靶点。为了解决这些假设，我们提出以下具体目标：1）表征由G-CSF受体远端域驱动的Lyn依赖性生长控制途径，并确定它们在原代MDS细胞中的存在； 2) 表征由于 IV 类 G-CSF 受体表达增加及其在原代 MDS 细胞中的存在而导致的信号传导变化； 3）在小鼠模型和细胞系中测试Lyn靶向治疗的效果。这些研究将为使用 Src 抑制剂治疗 MDS 患者亚型的 II 期研究提供依据。