Targeting SHP2 Phosphatase for Hematologic Malignancies in Noonan Syndrome

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（如青少年粒单核细胞白血病（JMML）、B细胞急性淋巴细胞白血病（B-ALL）和急性髓性白血病（AML））中发现了酪氨酸磷酸酶Ptpn 11（Shp 2）的种系和体细胞突变。这些突变导致Shp 2催化活性的过度活化。我们实验室和其他实验室的研究表明，Ptpn 11中的单一疾病突变足以导致小鼠努南综合征和JMML样骨髓增生性疾病，随后恶性进展为急性白血病，这表明Shp 2的过度激活在这些疾病中起着因果作用。Ptpn 11和努南综合征和儿童白血病的激活突变之间的直接联系表明，Shp 2可能是一个有用的目标，机制为基础的治疗，预防/治疗血液恶性肿瘤努南综合征。我们广泛的长期目标是确定Ptpn 11激活突变诱导努南综合征和儿童白血病的分子机制，并利用收集的信息开发这些疾病的新疗法。拟议项目的具体目的是验证Shp 2抑制剂，包括我们实验室鉴定的临床使用的天然产物药物，用于抑制Ptpn 11激活突变阳性白血病细胞。将测试Ptpn 11相关白血病的小鼠模型和JMML患者骨髓细胞。预计这项工作将建立使用Shp 2抑制剂预防和治疗努南综合征血液恶性肿瘤的基本原理。这些研究将极大地促进我们实验室发现的翻译，即，作为Shp 2抑制剂的已知临床使用的药物，用于临床试验。 公共卫生相关性：最近在发育障碍努南综合征和各种儿童白血病中发现了酪氨酸磷酸酶Ptpn 11（Shp 2）的种系和体细胞突变，导致Shp 2过度活跃。强有力的证据表明，Shp 2激活突变在驱动努南综合征的发展和血液恶性肿瘤进展。本申请中提出的项目旨在验证Shp 2抑制剂，包括我们实验室鉴定的临床使用的天然产物药物，抑制Shp 2激活突变阳性白血病细胞。将测试Shp 2相关白血病的小鼠模型和白血病患者骨髓细胞。预计这项工作将确立使用Shp 2抑制剂预防/治疗努南综合征血液恶性肿瘤的基本原理。这些研究将极大地促进我们实验室发现的翻译，即，作为Shp 2抑制剂的已知临床使用的药物，用于临床试验。

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.