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Targeting SHP2 Phosphatase for Hematologic Malignancies in Noonan Syndrome

靶向 SHP2 磷酸酶治疗努南综合征血液系统恶性肿瘤

基本信息

批准号：
8153435
负责人：
CHENG-KUI QU
金额：
$ 19.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-23 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8153435
关键词：
Acute Myelocytic Leukemia Acute leukemia Animal Disease Models Asians Automobile Driving B-Cell Acute Lymphoblastic Leukemia Biochemical Biological Biological Assay Biological Factors Bone Marrow Cells California Cell Differentiation process Cells Chemicals Chest Child Childhood Childhood Leukemia Clinical Clinical Trials Computer Assisted Country Databases Development Disease Disease Pathway Disease Progression Dose Drug Design Drug usage Dysmyelopoietic Syndromes Effectiveness Embryonic Development Face Gene Mutation Germ-Line Mutation Heart Diseases Hematologic Neoplasms Hematopoiesis Hematopoietic Heme Human In Vitro Induced Mutation Juvenile Myelomonocytic Leukemia Knock-in Mouse Laboratories Laboratory Finding Lead Legal patent Letters Malignant - descriptor Malignant Neoplasms Manuscripts Maryland Medicine Mental Retardation Modeling Molecular Molecular Biology Molecular Weight Mus Mutation Myelogenous Myeloproliferative disease Natural Product Drug Nature Non-Receptor Type 11 Protein Tyrosine Phosphatase Noonan Syndrome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Play Prevention Protein Tyrosine Phosphatase Resources Role Sampling San Francisco Screening procedure Signal Transduction Somatic Mutation Specificity Src homology 2 domain-containing, transforming protein 1 Stroke Structure Testing Therapeutic Toxicity Tests Translations Universities Ursidae Family Work base bone marrow hyperplasia computerized data processing congenital heart disorder design developmental disease efficacy testing high risk in vivo information gathering inhibitor/antagonist leukemia mouse model mutant novel novel therapeutics pediatrician prevent progenitor research study

项目摘要

DESCRIPTION (provided by applicant): Germline and somatic mutations in tyrosine phosphatase Ptpn11 (Shp2) have recently been identified in the developmental disorder Noonan syndrome and various childhood leukemias, such as juvenile myelomonocytic leukemia (JMML), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML). These mutations cause hyperactivation of Shp2 catalytic activity. Studies in our laboratory and others have demonstrated that a single disease mutation in Ptpn11 is sufficient to cause Noonan syndrome and JMML-like myeloid proliferative disease in mice followed by malignant progression to acute leukemias, suggesting that over activation of Shp2 plays a causal role in these diseases. Direct connection between activating mutations of Ptpn11 and Noonan syndrome and childhood leukemias indicates that Shp2 may be a useful target of mechanism-based therapeutics for preventing/treating hematologic malignancies in Noonan syndrome. Our broad, long-term objective is to determine the molecular mechanisms by which Ptpn11 activating mutations induce Noonan syndrome and childhood leukemias and to use the information gathered to develop novel therapeutics for these diseases. The specific aim of the proposed project is to validate the Shp2 inhibitors, including a clinically used natural product drug identified in our laboratory in suppressing Ptpn11 activating mutation-positive leukemia cells. Both a mouse model of Ptpn11-associated leukemias and JMML patient bone marrow cells will be tested. It is anticipated that this work will establish the rationale for using Shp2 inhibitors to prevent and treat hematologic malignancies in Noonan syndrome. These studies will greatly facilitate the translation of our laboratory finding, i.e., a known clinically used drug as a Shp2 inhibitor, to a clinical trial. PUBLIC HEALTH RELEVANCE: Germline and somatic mutations in tyrosine phosphatase Ptpn11 (Shp2) that cause Shp2 to be hyperactive have recently been identified in the developmental disorder Noonan syndrome and various childhood leukemias. Strong evidence implicates Shp2 activating mutations in driving the development and hematologic malignancy progression of Noonan syndrome. The project proposed in this application is designed to validate the Shp2 inhibitors, including a clinically used natural product drug identified in our laboratory, in suppressing Shp2 activating mutation-positive leukemia cells. Both a mouse model of Shp2- associated leukemias and leukemic patient bone marrow cells will be tested. It is anticipated that this work will establish the rationale for using Shp2 inhibitors to prevent/treat hematological malignancies in Noonan syndrome. These studies will greatly facilitate the translation of our laboratory finding, i.e., a known clinically used drug as a Shp2 inhibitor, to a clinical trial.

描述（由申请人提供）：最近在发育障碍努南综合征和各种儿童白血病中发现了酪氨酸磷酸酶 Ptpn11 (Shp2) 的种系和体细胞突变，例如幼年粒单核细胞白血病 (JMML)、B 细胞急性淋巴细胞白血病 (B-ALL) 和急性髓细胞白血病 (AML)。这些突变导致 Shp2 催化活性过度激活。我们实验室和其他实验室的研究表明，Ptpn11 中的单一疾病突变足以在小鼠中引起努南综合征和 JMML 样骨髓增殖性疾病，然后恶性进展为急性白血病，这表明 Shp2 的过度激活在这些疾病中起着因果作用。 Ptpn11 和努南综合征的激活突变与儿童白血病之间的直接联系表明，Shp2 可能是预防/治疗努南综合征血液恶性肿瘤的基于机制的治疗的有用靶点。我们广泛、长期的目标是确定 Ptpn11 激活突变诱发努南综合征和儿童白血病的分子机制，并利用收集到的信息开发针对这些疾病的新疗法。该项目的具体目标是验证Shp2抑制剂，包括我们实验室鉴定的临床使用的天然产物药物，可抑制Ptpn11激活突变阳性白血病细胞。 Ptpn11 相关白血病小鼠模型和 JMML 患者骨髓细胞都将进行测试。预计这项工作将为使用 Shp2 抑制剂预防和治疗努南综合征的血液恶性肿瘤奠定基础。这些研究将极大地促进我们的实验室发现（即已知的临床使用的 Shp2 抑制剂药物）转化为临床试验。公共健康相关性：最近在发育障碍努南综合征和各种儿童白血病中发现了导致 Shp2 过度活跃的酪氨酸磷酸酶 Ptpn11 (Shp2) 种系和体细胞突变。强有力的证据表明，Shp2 激活突变可驱动努南综合征的发生和血液恶性肿瘤进展。本申请中提出的项目旨在验证Shp2抑制剂（包括我们实验室鉴定的临床使用的天然产物药物）在抑制Shp2激活突变阳性白血病细胞方面的作用。将测试Shp2相关白血病的小鼠模型和白血病患者的骨髓细胞。预计这项工作将为使用 Shp2 抑制剂预防/治疗努南综合征的血液恶性肿瘤奠定基础。这些研究将极大地促进我们的实验室发现（即已知的临床使用的 Shp2 抑制剂药物）转化为临床试验。