Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia

用于治疗慢性粒细胞白血病的新型 SET 拮抗剂

基本信息

批准号：
8253135
负责人：
Dale J Christensen
金额：
$ 30万
依托单位：
ONCOTIDE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8253135
关键词：
Acute Lymphocytic Leukemia Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Applications Grants Binding Biological Assay Blast Phase Bone Marrow CD34 gene Cancer Cell Growth Caspase Cell Line Cell Proliferation Cells Chromosomal translocation Chromosome abnormality Chronic Myeloid Leukemia Chronic Phase Chronic-Phase Myeloid Leukemia Clinical Trials Dasatinib Data Disease Disease Resistance Disease model Dose Drug resistance Forskolin Funding Gleevec Grant Growth Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Human Imatinib In Vitro Inbred BALB C Mice Inflammatory Investigational New Drug Application K-562 Lead Leukemic Cell MAPK14 gene MAPK8 gene Mediating Modeling Molecular Mus Myeloproliferative disease Non-Hematologic Malignancy Oncogenes Oncogenic Patients Peptides Pharmacologic Substance Phase Philadelphia Chromosome Phosphorylation Phosphotransferases Positioning Attribute Preparation Principal Investigator Production Protein Dephosphorylation Protein Overexpression Protein Tyrosine Kinase Protein phosphatase Proteins Proto-Oncogene Proteins c-akt Reporting Resistance Role STAT5A gene Scientist Signal Transduction Signaling Protein Stem cells System Testing Therapeutic Toxic effect Toxicology Transplantation Tumor Suppression Tumor Suppressor Proteins Tyrosine Kinase Inhibitor alternative treatment base bcr-abl Fusion Proteins cancer cell cell growth cytotoxic cytotoxicity experience human BCR protein improved in vitro activity in vivo in vivo Model inhibitor/antagonist kinase inhibitor leukemia mouse model multicatalytic endopeptidase complex novel overexpression prevent progenitor protein phosphatase 2A inhibitor 2 response small hairpin RNA tool treatment strategy

项目摘要

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.

描述（由申请人提供）：慢性粒细胞白血病（CML）影响着全世界近 14,000 名患者，是一种具有两个不同阶段的多能造血干细胞疾病。旷日持久的骨髓增生慢性期之后是迅速致命的急变期。在 CML 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 激酶的组成型激活形式。 Abl 的这种组成型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，CML 的治疗取得了进展，但最近报道了格列卫耐药性 CML，并日益引起人们的关注。进入急变期的患者也会经历对格列卫和其他 BCR/ABL 抑制剂（即达沙替尼和尼罗替尼）的耐药性。最近，Perrotti 和同事证明，BCR/ABL 活性水平的增加也会导致急变期中蛋白质 SET 的过度表达由于其对肿瘤抑制蛋白磷酸酶 2A 的有效抑制作用，可用于 CML 阶段和 PH1(+) 急性淋巴细胞白血病。 (PP2A) SET 被称为蛋白磷酸酶 2A 抑制剂 (I2PP2A)，SET 的过度表达会导致 PP2A 的强烈抑制，从而抑制 PP2A 通过去磷酸化发挥其失活信号蛋白的调节作用。新化合物）在体外和体内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 结合并能够激活细胞中的 PP2A 酶活性。基于这些数据，我们推测我们的先导化合物 (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。我们已确定 OP449 在 BCR/ABL+ K562 CML 系中抑制增殖并诱导细胞凋亡，抑制原代患者来源的 CML 细胞的集落形成，并且对正常 CD34+ 细胞没有细胞毒性。我们现在寻求扩展这些研究，以确定 OP449 对耐药 CML 细胞和急变期 CML 细胞是否具有细胞毒性；评估这些细胞中 PP2A 的激活；确定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。公共健康相关性：慢性粒细胞白血病 (CML) 影响着全球近 14,000 名患者，是一种具有两个不同阶段的多能造血干细胞疾病。旷日持久的骨髓增生慢性期之后是迅速致命的急变期。在 CML 中，一种称为费城染色体 (Ph1) 的染色体异常会导致细胞中的信号系统卡在开启位置，而无法打开和关闭。当卡在开启位置时，会导致 CML。尽管随着格列卫和其他异常信号蛋白抑制剂的引入，CML 的治疗取得了进展，但最近有报道称，格列卫耐药性 CML 引起了越来越多的关注。在研究响应卡住信号而打开的信号时，发现一种称为 SET 的蛋白质在 CML 细胞中积聚，这会破坏控制细胞生长和增殖的称为 PP2A 的蛋白质的功能。最近，我们发现了一些小化合物，可以使蛋白质 SET 失活并恢复 PP2A 的正常功能，并发现这些化合物可以阻止 CML 和其他癌细胞的生长。基于这些数据，我们假设 Oncotide 的化合物可能为 CML 患者提供治疗益处。该拨款提案获得的资金将用于确定其中一些化合物是否可以抑制 CML 患者癌细胞的生长，并阻止 CML 小鼠模型中癌细胞的生长。