Novel Targeted Therapy for CLL

CLL 的新型靶向治疗

基本信息

批准号：
7612201
负责人：
Dale J Christensen
金额：
$ 25.71万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612201
关键词：
11q Accounting Acute Affinity Age Amino Acids Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Apolipoprotein E Apoptosis B-Lymphocytes Binding Biological Blood Bone Marrow Buffers CD19 gene Cell Count Cell Cycle Regulation Cell Survival Cells Cholesterol Homeostasis Chromosome abnormality Chronic Lymphocytic Leukemia Clinical Clinical Trials Complement Factor B Cytolysis Daily Data Development Disease Dose Endopeptidases Evaluation First Degree Relative Gene Mutation Genetic Predisposition to Disease Genetic Transcription Grant Human Immunoblotting In Vitro Inflammation Inflammatory Inhibition of Apoptosis Investigational New Drug Application Lead Leukocytes Liver Lymphocyte Count MAPK14 gene MAPK8 gene Malignant - descriptor Mature B-Lymphocyte Measures Mitogen-Activated Protein Kinases Monitor Mus NOS2A gene Nuclear Oncogenes Orphan Outcome PPP2R1B gene Pathway interactions Patients Peptide Hydrolases Peptides Personal Satisfaction Phase Phase I Clinical Trials Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Population Preparation Principal Investigator Production Property Protein Binding Protein Dephosphorylation Protein Overexpression Protein phosphatase Proteins Public Health Relative (related person)Risk Factors Role Safety Sampling Severities Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Signaling Protein Spleen Surface Immunoglobulins Survival Rate Testing Therapeutic Toxicology Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins United States Food and Drug Administration Weight Western World abl Oncogene adult leukemia base cytokine cytotoxic day design expectation human IRAK1 protein human NOS2A protein human PPP2R1B protein improved in vivo inhibitor/antagonist insight killings leukemia leukemogenesis lymph nodes mimetics mitogen-activated protein kinase p38 mouse model neoplastic cell normal aging novel novel strategies novel therapeutics phosphatase inhibitor protein phosphatase 2A regulatory subunit 65 kDa protein phosphatase inhibitor-2 selective expression treatment duration volunteer

项目摘要

DESCRIPTION (provided by applicant): Of the nearly 84,000 cases of leukemia in the Western world, B-cell chronic lymphocytic leukemia (B-CLL) is the most common and accounts for approximately 30% of all adult leukemia cases. It is characterized by the relentless accumulation of monoclonal mature B cells. Tumor cells from B-CLL patients show increased survival rates that have been shown to be due to inhibited apoptosis and alterations of genes involved in cell cycle control and cell survival. When evaluating the signaling pathways that are aberrantly activated in B-CLL cells, it was demonstrated that the kinase Akt is constitutively activated and the overstimulation of Akt results in activation of the NFkB pathway that leads to increased production of NO and inhibited apoptosis. It has been known for many years that a genetic predisposition for B-CLL exists given that B-CLL occurs more commonly in people with at least one first degree relative with CLL. Among chromosomal aberrations that have been documented in B-CLL cases is a deletion at 11q that includes a portion of the PPP2R1B gene, which encodes the A2 constant regulatory subunit of Protein Phosphatase 2a (PP2a). PP2a is a commonly known tumor suppressor that is underexpressed as a result of the 11q deletion leading to decreased PP2a activity in B-CLL cells. The role of PP2a in deactivation of Akt, the mitogen activated protein kinases (MAPK) p38, JNK, and ERK, as well as Nuclear Factor kB (through IkK) is well established. Reduced PP2a activity in B-CLL cells would be expected to lead to aberrant signaling through Akt, production of inducible Nitric Oxide Synthase (iNOS), and other effects demonstrated in malignant B-CLL cells. Therefore, pharmacological activation of PP2a may provide a novel approach to development of B-CLL therapeutics. Cognosci has developed novel therapeutic peptides with potent anti-inflammatory activity in vitro and in vivo. In mechanistic studies we recently demonstrated that these peptides suppress phosphorylation and the accompanying activation of important inflammatory signaling proteins including p38, JNK, and ERK MAPKs as well as IkK, IkB, and NFkB. Upon analysis of the mechanism of action of the Cognosci compounds, we found that compound treatment results in activation of PP2a and suppression of signal transduction pathways and production of cytokines, iNOS and its product NO. During a preliminary evaluation of several COG compounds in primary CD19+/CD5+ B-CLL cells from patients, we discovered that one of these compounds, (COG112) is highly and preferentially cytotoxic for human CLL cells with an EC50 of 224 nM and an EC50 for normal B-cells of >20 uM. We propose to determine the effect of COG112 treatment on the phosphorylation state of key signal transduction proteins and PP2a activity in B-CLL cells. We will also evaluate COG112 for anti-CLL activity in the E5-TCL1 transgenic mouse model of CLL. PUBLIC HEALTH RELEVANCE: Of the nearly 84,000 cases of leukemia in the Western world, B-cell chronic lymphocytic leukemia (B-CLL) is the most common and accounts for approximately 30% of all adult leukemia cases. It is characterized by the relentless accumulation of monoclonal mature B cells. Tumor cells from B-CLL patients show increased survival rates that have been shown to be due to inhibited apoptosis and alterations of genes involved in cell cycle control and cell survival. When evaluating the signaling pathways that are aberrantly activated in B-CLL cells, it was demonstrated that the kinase Akt is constitutively activated and the overstimulation of Akt results in activation of the NFkB pathway that leads to increased production of NO and inhibited apoptosis. It has been known for many years that a genetic predisposition for B-CLL exists given that B-CLL occurs more commonly in people with at least one first degree relative with CLL. Among chromosomal aberrations that have been documented in B-CLL cases is a deletion at 11q that includes a portion of the PPP2R1B gene, which encodes the A2 constant regulatory subunit of Protein Phosphatase 2a (PP2a). PP2a is a commonly known tumor suppressor that is underexpressed as a result of the 11q deletion leading to decreased PP2a activity in B-CLL cells. The role of PP2a in deactivation of Akt, the mitogen activated protein kinases (MAPK) p38, JNK, and ERK, as well as Nuclear Factor kB (through IkK) is well established. Reduced PP2a activity in B-CLL cells would be expected to lead to aberrant signaling through Akt, production of inducible Nitric Oxide Synthase (iNOS), and other effects demonstrated in malignant B-CLL cells. Therefore, pharmacological activation of PP2a may provide a novel approach to development of B-CLL therapeutics. Cognosci has developed novel therapeutic peptides with potent anti-inflammatory activity in vitro and in vivo. In mechanistic studies we recently demonstrated that these peptides suppress phosphorylation and the accompanying activation of important inflammatory signaling proteins including p38, JNK, and ERK MAPKs as well as IkK, IkB, and NFkB. Upon analysis of the mechanism of action of the Cognosci compounds, we found that compound treatment results in activation of PP2a and suppression of signal transduction pathways and production of cytokines, iNOS and its product NO. During a preliminary evaluation of several COG compounds in primary CD19+/CD5+ B-CLL cells from patients, we discovered that one of these compounds, (COG112) is highly and preferentially cytotoxic for human CLL cells with an EC50 of 224 nM and an EC50 for normal B-cells of >20 uM. We propose to determine the effect of COG112 treatment on the phosphorylation state of key signal transduction proteins and PP2a activity in B-CLL cells. We will also evaluate COG112 for anti-CLL activity in the E5-TCL1 transgenic mouse model of CLL.

描述（申请人提供）：在西方世界近 84,000 例白血病病例中，B 细胞慢性淋巴细胞白血病 (B-CLL) 是最常见的，约占所有成人白血病病例的 30%。其特点是单克隆成熟 B 细胞不断积累。 B-CLL 患者的肿瘤细胞表现出较高的存活率，这已被证明是由于细胞凋亡受到抑制以及参与细胞周期控制和细胞存活的基因改变所致。当评估 B-CLL 细胞中异常激活的信号通路时，结果表明激酶 Akt 被组成型激活，Akt 的过度刺激会导致 NFkB 通路的激活，从而导致 NO 产生增加并抑制细胞凋亡。多年来，人们已经知道 B-CLL 存在遗传倾向，因为 B-CLL 更常见于至少有一名一级亲属患有 CLL 的人群。 B-CLL 病例中记录的染色体畸变包括 11q 处的缺失，其中包括 PPP2R1B 基因的一部分，该基因编码蛋白磷酸酶 2a (PP2a) 的 A2 恒定调节亚基。 PP2a 是一种众所周知的肿瘤抑制因子，由于 11q 缺失导致 B-CLL 细胞中 PP2a 活性降低，导致 PP2a 表达不足。 PP2a 在 Akt、丝裂原激活蛋白激酶 (MAPK) p38、JNK 和 ERK 以及核因子 kB（通过 Ikk）失活中的作用已得到充分证实。 B-CLL 细胞中 PP2a 活性的降低预计会导致 Akt 信号传导异常，产生诱导型一氧化氮合酶 (iNOS)，以及在恶性 B-CLL 细胞中表现出的其他效应。因此，PP2a 的药理学激活可能为 B-CLL 治疗的开发提供一种新方法。 Cognosci 开发了新型治疗肽，在体外和体内均具有有效的抗炎活性。在机制研究中，我们最近证明这些肽可抑制重要炎症信号蛋白的磷酸化和伴随的激活，包括 p38、JNK 和 ERK MAPK 以及 IkK、IkB 和 NFkB。通过分析 Cognosci 化合物的作用机制，我们发现化合物治疗会激活 PP2a，并抑制信号转导途径和细胞因子、iNOS 及其产物 NO 的产生。在对患者原代 CD19+/CD5+ B-CLL 细胞中的几种 COG 化合物进行初步评估时，我们发现其中一种化合物 (COG112) 对人类 CLL 细胞具有高度且优先的细胞毒性，EC50 为 224 nM，EC50 >20 uM 的正常 B 细胞。我们建议确定 COG112 治疗对 B-CLL 细胞中关键信号转导蛋白磷酸化状态和 PP2a 活性的影响。我们还将评估 COG112 在 CLL E5-TCL1 转基因小鼠模型中的抗 CLL 活性。公共卫生相关性：在西方世界近 84,000 例白血病病例中，B 细胞慢性淋巴细胞白血病 (B-CLL) 是最常见的，约占所有成人白血病病例的 30%。其特点是单克隆成熟 B 细胞不断积累。 B-CLL 患者的肿瘤细胞表现出较高的存活率，这已被证明是由于细胞凋亡受到抑制以及参与细胞周期控制和细胞存活的基因改变所致。当评估 B-CLL 细胞中异常激活的信号通路时，结果表明激酶 Akt 被组成型激活，Akt 的过度刺激会导致 NFkB 通路的激活，从而导致 NO 产生增加并抑制细胞凋亡。多年来，人们已经知道 B-CLL 存在遗传倾向，因为 B-CLL 更常见于至少有一名一级亲属患有 CLL 的人群。 B-CLL 病例中记录的染色体畸变包括 11q 处的缺失，其中包括 PPP2R1B 基因的一部分，该基因编码蛋白磷酸酶 2a (PP2a) 的 A2 恒定调节亚基。 PP2a 是一种众所周知的肿瘤抑制因子，由于 11q 缺失导致 B-CLL 细胞中 PP2a 活性降低，导致 PP2a 表达不足。 PP2a 在 Akt、丝裂原激活蛋白激酶 (MAPK) p38、JNK 和 ERK 以及核因子 kB（通过 Ikk）失活中的作用已得到充分证实。 B-CLL 细胞中 PP2a 活性的降低预计会导致 Akt 信号传导异常，产生诱导型一氧化氮合酶 (iNOS)，以及在恶性 B-CLL 细胞中表现出的其他效应。因此，PP2a 的药理学激活可能为 B-CLL 治疗的开发提供一种新方法。 Cognosci 开发了新型治疗肽，在体外和体内均具有有效的抗炎活性。在机制研究中，我们最近证明这些肽可抑制重要炎症信号蛋白的磷酸化和伴随的激活，包括 p38、JNK 和 ERK MAPK 以及 IkK、IkB 和 NFkB。通过分析 Cognosci 化合物的作用机制，我们发现化合物治疗会激活 PP2a，并抑制信号转导途径和细胞因子、iNOS 及其产物 NO 的产生。在对患者原代 CD19+/CD5+ B-CLL 细胞中的几种 COG 化合物进行初步评估时，我们发现其中一种化合物 (COG112) 对人类 CLL 细胞具有高度且优先的细胞毒性，EC50 为 224 nM，EC50 >20 uM 的正常 B 细胞。我们建议确定 COG112 治疗对 B-CLL 细胞中关键信号转导蛋白磷酸化状态和 PP2a 活性的影响。我们还将评估 COG112 在 CLL E5-TCL1 转基因小鼠模型中的抗 CLL 活性。