Targeting of Tyrosine Phosphatase SHP2 in Myeloproliferative Neoplasms

 描述（由申请方提供）：骨髓增生性肿瘤（MPN）包括真性红细胞增多症（PV）、原发性血小板增多症（ET）和原发性骨髓纤维化（PMF），是以髓系细胞过度生成为特征的慢性髓系恶性肿瘤。获得性JAK 2 V617 F突变导致JAK 2酪氨酸激酶的组成性激活，已在大多数MPN患者中发现。这导致了JAK 2抑制剂的开发。Ruxolitinib是一种JAK 1/JAK 2抑制剂，已被批准用于治疗抗羟基脲的PV和晚期MF。虽然Ruxolitinib治疗可以减少脾肿大和全身症状，但它未能在PV/MF患者中产生完全缓解。已经清楚的是，目前包括JAK 2抑制剂的化疗不足以治愈MPN。因此，迫切需要开发针对MPN的新型靶向疗法。我们已经发现，在表达JAK 2 V617 F的小鼠和人MPN细胞中，SHP 2是组成性磷酸化/活化的。SHP 2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SHP 2的敲低显著抑制表达JAK 2 V617 F的细胞的增殖。此外，SHP 2的缺失抑制了JAK 2 V617 F基因敲入小鼠中PV和MF的发展。此外，用新型SHP 2抑制剂11 a-1处理显著抑制JAK 2 V617 F阳性MPN细胞的生长。因此，我们推测SHP 2可能在JAK 2 V617 F诱导的造血转化/MPN中起重要作用，并且药物抑制SHP 2可能对MPN有效。为了验证我们的假设，我们提出了两个具体目标。在目标1中，我们将使用floxed SHP 2和条件性JAK 2 V617 F敲入小鼠进一步确定SHP 2在PV和MF的发展和维持中的作用。在目标2中，我们将确定新型SHP 2抑制剂11 a-1对培养的和原代MPN细胞以及PV和MF动物模型的安全性和有效性。我们还将确定SHP 2缺失或抑制对JAK 2 V617 F诱发的信号传导的影响，并确定SHP 2调节JAK 2 V617 F诱导的转化/MPN的机制。我们提出的研究将首次证明SHP 2在MPN（PV和MF）的发展中起重要作用，并且使用小分子抑制剂11 a-1靶向SHP 2是治疗MPN的新策略。此外，这些临床前研究的结果将为SHP 2抑制剂11 a-1治疗MPN的I/II期临床试验提供支持性数据。

 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.