Targeting of Tyrosine Phosphatase SHP2 in Myeloproliferative Neoplasms

酪氨酸磷酸酶 SHP2 在骨髓增生性肿瘤中的靶向作用

• 批准号: 9025334
• 负责人: Golam Mohi
• 金额: $ 22.49万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-17 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025334
• 关键词: Animal Model; Applications Grants; Cancer Center; Cell Line; Cell Lineage; Cell Proliferation; Cells; Chronic; Clinical; Clinical Trials; Constitutional Symptom; Data; Development; Disease; Disease remission; Exhibits; Genetic; Goals; Growth; Hematology; Hematopoietic; Hemorrhagic Thrombocythemia; Human; In complete remission; JAK1 gene; JAK2 gene; Knock-in Mouse; LoxP-flanked allele; Maintenance; Mediating; Molecular; Mus; Mutation; Myelogenous; Myeloproliferative disease; PTPN11 gene; Pathogenesis; Patients; Penetrance; Phase; Play; Polycythemia Vera; Pre-Clinical Model; Primary Myelofibrosis; Production; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Research; Research Personnel; Resistance; Role; Safety; Sampling; Signal Transduction; Splenomegaly; Testing; University Hospitals; Work; Yin; base; chemotherapy; drug discovery; efficacy testing; expectation; hydroxyurea; inhibitor/antagonist; knock-down; mouse model; new therapeutic target; novel; novel strategies; preclinical study; prevent; progenitor; public health relevance; small molecule inhibitor

 DESCRIPTION (provided by applicant): Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are chronic myeloid malignancies characterized by overproduction of myeloid lineage cells. An acquired JAK2V617F mutation, which results in constitutive activation of the JAK2 tyrosine kinase, has been found in a majority of patients with MPNs. This has led to the development of JAK2 inhibitors. Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for treatment of hydroxyurea-resistant PV and advanced MF. Although Ruxolitinib therapy can reduce splenomegaly and constitutional symptoms, it failed to produce complete remission in patients with PV/MF. It has become clear that current chemotherapies including JAK2 inhibitors are not sufficient to cure MPNs. So, there is a critical need to develop novel targeted therapies for MPNs. We have found that SHP2 is constitutively phosphorylated/activated in mouse and human MPN cells expressing JAK2V617F. SHP2 is a protein tyrosine phosphatase that plays a positive role in cell signaling. In preliminary studies, we have observed that knockdown of SHP2 significantly inhibits proliferation of cells expressing JAK2V617F. Moreover, deletion of SHP2 inhibits the development of PV and MF in JAK2V617F knock-in mice. Furthermore, treatment with a novel SHP2 inhibitor 11a-1 significantly inhibits the growth of JAK2V617F-positive MPN cells. So, we hypothesize that SHP2 may play important roles in hematopoietic transformation/MPNs induced by JAK2V617F, and pharmacologic inhibition of SHP2 might be efficacious against MPNs. To test our hypothesis, we have proposed two specific aims. In Aim 1, we will further define the role of SHP2 in the development and maintenance of PV and MF using floxed SHP2 and conditional JAK2V617F knock-in mice. In Aim 2, we will determine the safety and efficacy of a novel SHP2 inhibitor 11a-1 against cultured and primary MPN cells and animal models of PV and MF. We will also determine the effects of SHP2 deletion or inhibition on JAK2V617F-evoked signaling and define the mechanism by which SHP2 regulates JAK2V617F-induced transformation/MPNs. Our proposed studies will provide the first demonstration that SHP2 plays an important role in the development of MPNs (PV and MF) and targeting of SHP2 using small molecule inhibitor 11a-1 is a novel strategy in treating MPNs. Moreover, results from these pre-clinical studies will generate the supportive data for Phase I/II clinical trials of SHP2 inhibitor 11a-1 in the treatment of MPNs.

 描述（由适用提供）：包括多性细胞增多症（PV），必需血小板细胞增多症（ET）和原发性骨髓纤维纤维化（PMF），包括慢性髓样恶性肿瘤，其特征是髓样细胞的过度产生特征。在大多数MPN患者中发现了一种获得的JAK2V617F突变，导致JAK2酪氨酸激酶的组成型激活。这导致了JAK2抑制剂的发展。 ruxolitinib是一种JAK1/JAK2抑制剂，已批准用于治疗耐羟基脲的PV和Advanced MF。尽管鲁唑替尼治疗可以减少脾肿大和宪法症状，但在PV/MF患者中未能完全缓解。很明显，包括JAK2抑制剂在内的当前化学疗法不足以治愈MPN。因此，迫切需要开发新颖的MPN靶向疗法。我们发现，在表达JAK2V617F的小鼠和人MPN细胞中，SHP2是组成型磷酸化/激活的。 SHP2是一种蛋白酪氨酸磷酸酶，在细胞信号传导中起积极作用。在初步研究中，我们观察到SHP2的敲低显着抑制了表达JAK2V617F的细胞的增殖。此外，SHP2的缺失抑制了JAK2V617F敲入小鼠中PV和MF的发展。此外，使用新型SHP2抑制剂11A-1处理可显着抑制JAK2V617F阳性MPN细胞的生长。因此，我们假设SHP2可能在JAK2V617F诱导的造血转化/MPN中起重要作用，而SHP2的药物抑制可能对MPN有效。为了检验我们的假设，我们提出了两个具体目标。在AIM 1中，我们将进一步定义SHP2在使用Floxed SHP2和有条件的JAK2V617F敲入小鼠的开发和维护中的作用。在AIM 2中，我们将确定新型SHP2抑制剂11A-1对PV和MF的培养和原代MPN细胞以及动物模型的安全性和有效性。我们还将确定SHP2缺失或抑制对JAK2V617F诱发的信号的影响，并定义SHP2调节JAK2V617F诱导的转换/MPN的机制。我们提出的研究将提供首次证明，即SHP2在MPN（PV和MF）的发展中起重要作用，并使用小分子抑制剂11A-1对SHP2的靶向是治疗MPN的新型策略。此外，这些临床前研究的结果将生成SHP2抑制剂11A-1阶段临床试验的支持数据，以治疗MPN。