Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia

描述（由申请人提供）：慢性髓性白血病（CML）是一种多能性造血干细胞疾病，有两个不同的阶段，在全球范围内影响近14000名患者。延长的髓细胞增殖慢性期之后是迅速致命的细胞危象。在慢性粒细胞白血病中，染色体易位导致费城染色体（Ph1）的产生，其中BCR蛋白与Abl激酶融合形成BCR/ Abl癌基因，这是Abl激酶的组成性激活形式。这种Abl的组成性激活已被证明足以诱导慢性期CML。尽管随着格列卫和其他BCR/ABL抑制剂的引入，慢性粒细胞白血病的治疗取得了进展，但最近有报道称，格列卫耐药的慢性粒细胞白血病日益受到关注。进入母细胞期的患者也会对格列卫和其他BCR/ABL抑制剂（即达沙替尼和尼洛替尼）产生耐药性。最近，Perrotti和同事证明BCR/ABL活性水平的增加也会导致CML细胞期和PH1（+）急性淋巴细胞白血病中SET蛋白的过度表达。由于其对肿瘤抑制蛋白磷酸酶2A （PP2A）的有效抑制，SET被称为蛋白磷酸酶2A （I2PP2A）的抑制剂-2。SET过表达导致PP2A的强烈抑制，从而抑制PP2A通过去磷酸化使信号蛋白失活的调节能力。Oncotide制药公司已经开发出新的化合物，在体外和体内都具有有效的抗炎活性。在机制研究中，我们最近发现这些肽与SET结合并具有激活细胞中PP2A酶活性的能力。基于这些数据，我们假设我们的先导化合物（OP449）可能为CML和其他以PP2A活性受损为特征的血液和非血液恶性肿瘤患者提供治疗益处。我们已经确定OP449在BCR/ABL+ K562 CML细胞系中抑制增殖和诱导凋亡，抑制原代患者源性CML细胞的集落形成，并且对正常CD34+细胞无细胞毒性。我们现在寻求扩展这些研究，以确定OP449是否对耐药CML细胞和母细胞期CML细胞具有细胞毒性；评估这些细胞中PP2A的激活素；测定OP449处理对BCR/ABL、ERK、AKT和STAT5磷酸化的影响；抑制CML体内模型的生长。

DESCRIPTION (provided by applicant): Chronic Myelogenous Leukemia (CML) affects nearly 14,000 patients worldwide and is a disorder of the pluripotent hematopoietic stem cells with two distinct phases. The protracted myelopoliferative chronic phase is followed by a rapidly fatal blast crisis. In CML, a chromosomal translocation leads to production of the Philadelphia Chromosome (Ph1) in which the BCR protein is fused to the Abl kinase to form the BCR/ABL oncogene, a constitutively activated form of the Abl kinase. This constitutive activation of Abl has been shown to be sufficient for induction of chronic phase CML. Although progress has been made in treatment of CML with the introduction of Gleevec and other inhibitors of BCR/ABL, recently however, Gleevec resistant CML has been reported and is a growing concern. Patients that progress into blast phase also experience a resistance to Gleevec and other BCR/ABL inhibitors (i.e. dasatinib and nilotinib. Recently, Perrotti and coworkers demonstrated that increased levels of BCR/ABL activity also results in the overexpression of the protein SET in the blast phase of CML and in the PH1(+) acute lymphoblastic leukemia. Due to its potent inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A) SET is known as Inhibitor-2 of Protein Phosphatase 2A (I2PP2A). Overexpression of SET results in strong inhibition of PP2A, thereby inhibiting the ability of PP2A to perform its regulatory role in deactivating signaling proteins by dephosphorylation. Oncotide Pharmaceuticals has developed novel compounds) that have potent anti-inflammatory activity in vitro and in vivo. In mechanistic studies we recently discovered that these peptides bind to SET and have the ability to activate PP2A enzymatic activity in the cell. Based on this data, we postulated that our lead compound (OP449) may provide therapeutic benefits in patients with CML and other hematologic and non-hematologic malignancies characterized by impaired PP2A activity. We have determined that OP449 suppresses proliferation and induces apoptosis in the BCR/ABL+ K562 CML line, inhibits colony formation by primary patient-derived CML cells, and does is not cytotoxic to normal CD34+ cells. We now seek to extend these studies to determine if OP449 is cytotoxic to drug-resistant CML cells and blast phase CML cells; evaluate the activatin of PP2A in these cells; determine the effect of OP449 treatment on phosphorylation of BCR/ABL, ERK, AKT and STAT5; an inhibit growth in an in vivo model of CML. PUBLIC HEALTH RELEVANCE: Chronic Myelogenous Leukemia (CML) effects nearly 14,000 patients worldwide and is a disorder of the pluripotent hematopoietic stem cells with two distinct phases. The protracted myelopoliferative chronic phase is followed by a rapidly fatal blast crisis. In CML, a chromosomal abnormality known as the Philadelphia Chromosome (Ph1) leads to a signal system in the cell being stuck in the on position instead of being able to be turned on and off. When stuck in the on position it causes CML. Although progress has been made in treatment of CML with the introduction of Gleevec and other inhibitors of the abnormal signal protein, recently however, Gleevec resistant CML has been reported and is a growing concern. While investigating the signals that are turned on in response to the stuck signal, it has been discovered that a protein known as SET accumulates in the CML cells and this disrupts the function of a protein known as PP2A that controls cell growth and proliferation. Recently we discovered small compounds that deactivate the protein SET and restore the normal function of PP2A and have found that these compounds block the growth of CML and other cancer cells. Based on these data, we hypothesize that Oncotide's compounds may provide a therapeutic benefit to patients with CML. The funds derived from this grant proposal will be utilized to determine if some of these compounds can inhibit growth of cancer cells from CML patients and stop the growth of cancer cells in a mouse model of CML.