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）：骨髓增生性综合征（MDS）是一种疾病，频率增加，对其病理生理学的了解不足，没有治愈性疗法缺乏同种异体干细胞移植。由于大多数患者是老年人，因此迫切需要新的治疗策略。 MD从失调的克隆造血疾病演变为急性髓样白血病（AML）。在早期MDS中，高细胞骨髓中血细胞的凋亡加速。在晚期MDS中，细胞凋亡是不足的，并且会发生分化的阻滞。我们的实验室一直在研究由粒细胞刺激因子（G-CSF）刺激的细胞中的信号传导途径。 G-CSF受体信号异常以几种形式的儿科和成年MDS发现：1）严重的先天性中性粒细胞减少症患者患MDS/AML的风险增加了10,000倍 - 几乎所有人都表达了截断的G-CSF受体； 2）在AML，MDS和Monosomy 7患者中，分化缺陷的G-CSF受体同工型的表达升高； 3）在MDS患者中发生了影响G-CSF受体远端的功能多态性。因此，我们假设由于功能失调的G-CSF受体信号传导导致的骨髓病失调是MDS的某些病例，而靶向治疗可能会成功延迟或防止白血病转化。我们已经将SRC激酶LYN确定为G-CSF受体信号传导的主要效应子。 Lyn主要限于血细胞，提供了可行的药物靶标。为了解决这些假设，我们提出了以下特定目的：1）表征由G-CSF受体远端域驱动的Lyn依赖性生长途径，并确定它们在原代MDS细胞中的存在； 2）表征由于IV类G-CSF受体的表达增加而引起的信号传导变化及其在原代MDS细胞中的存在； 3）测试LYN靶向治疗在小鼠模型和细胞系中的影响。这些研究将为使用SRC抑制剂用于MDS患者的亚群提供II期研究的基本原理。