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

• 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
• 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

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）：慢性骨髓性白血病（CML）影响全球近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。慢性骨髓增生期延长后会出现快速致命的急变。在CML中，染色体易位导致产生费城染色体（Ph 1），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的这种组成性激活已被证明足以诱导慢性期CML。虽然随着格列卫和其他BCR/ABL抑制剂的引入，CML的治疗取得了进展，但最近，格列卫耐药CML已被报道，并日益受到关注。进展到急变期的患者也经历了对格列卫和其他BCR/ABL抑制剂（即达沙替尼和尼洛替尼）的耐药性。最近，Perrotti及其同事证明BCR/ABL活性水平的增加也导致CML急变期和PH 1（+）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（PP 2A）的有效抑制，SET被称为蛋白磷酸酶2A（I2 PP 2A）的抑制剂-2。SET的过表达导致PP 2A的强烈抑制，从而抑制PP 2A通过去磷酸化在使信号蛋白失活中发挥其调节作用的能力。Oncotide Pharmaceuticals已经开发了在体外和体内具有有效抗炎活性的新型化合物。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PP 2A酶活性的能力。基于这些数据，我们假设我们的先导化合物（OP 449）可以为CML以及其他以PP 2A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，OP 449在BCR/ABL+ K562 CML细胞系中抑制增殖并诱导凋亡，抑制原代患者源性CML细胞的集落形成，并且对正常CD 34+细胞没有细胞毒性。我们现在试图扩展这些研究，以确定OP 449是否对耐药CML细胞和急变期CML细胞具有细胞毒性;评估这些细胞中PP 2A的活化;确定OP 449治疗对BCR/ABL、ERK、AKT和STAT 5磷酸化的影响;在体内CML模型中抑制生长。 公共卫生相关性：慢性粒细胞白血病（CML）影响全世界近14，000名患者，并且是具有两个不同阶段的多能造血干细胞的病症。慢性骨髓增生期延长后会出现快速致命的急变。 在CML中，被称为费城染色体（Ph 1）的染色体异常导致细胞中的信号系统被卡在打开位置，而不是能够打开和关闭。当卡在打开位置时，它会导致CML。尽管随着格列卫和其他异常信号蛋白抑制剂的引入，CML的治疗已经取得了进展，然而，最近已经报道了格列卫耐药CML，并且越来越受到关注。在研究响应于卡住信号而打开的信号时，已经发现称为SET的蛋白质在CML细胞中积累，并且这破坏了称为PP 2A的蛋白质的功能，该蛋白质控制细胞生长和增殖。最近，我们发现了一些小的化合物，可以使SET蛋白失活并恢复PP 2A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。来自该拨款提案的资金将用于确定这些化合物中的一些是否可以抑制CML患者的癌细胞生长，并阻止CML小鼠模型中癌细胞的生长。