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（由申请人提供）：在西方世界中近84,000例白血病中，B细胞慢性淋巴细胞性白血病（B-CLL）最常见，约占所有成人白血病病例的30％。它的特征是单克隆成熟B细胞的无情积累。来自B-CLL患者的肿瘤细胞显示出增加的存活率，这已证明是由于抑制凋亡以及与细胞周期控制和细胞存活有关的基因的改变。在评估在B-CLL细胞中异常激活的信号传导途径时，证明激酶AKT是组成型激活的，AKT的过度刺激导致NFKB途径的激活，从而导致NO和抑制凋亡的产生增加。多年来，鉴于B-CLL的遗传易感性在至少一个具有CLL的一级相对的人中更常见，因此存在B-CLL的遗传易感性。在B-CLL病例中已记录的染色体畸变中，有11Q的缺失，其中包括一部分PPP2R1B基因，该基因编码了蛋白磷酸酶2a（PP2A）的A2恒定调节亚基。 PP2A是一种众所周知的肿瘤抑制剂，由于11Q缺失导致B-CLL细胞中PP2A活性降低而受到抑制。 PP2A在AKT，有丝分裂激活的蛋白激酶（MAPK）P38，JNK和ERK以及核因子KB（通过IKK）中的作用。预计B-CLL细胞中PP2A活性的降低将通过AKT，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果导致异常信号传导。因此，PP2A的药理激活可能为B-CLL疗法的开发提供了一种新颖的方法。 Cognosci在体外和体内开发了具有有效的抗炎活性的新型治疗肽。在机械研究中，我们最近表明，这些肽抑制磷酸化以及包括p38，JNK和ERK MAPK以及IKK，IKB和NFKB在内的重要炎症信号蛋白的伴随激活。通过分析Cognosci化合物的作用机理，我们发现化合物治疗会导致PP2A的激活和信号转导途径的抑制以及细胞因子，INOS及其产物NO的产生。在对患者原代CD19+/CD5+ B-CLL细胞中几种COG化合物进行初步评估时，我们发现，对于正常B-Cells的EC50的EC50，EC50的EC50的EC50高度高，优先且优先为EC50的EC50和EC50的EC50> 20 UM的EC50。我们建议确定COG112处理对B-CLL细胞中关键信号转导蛋白和PP2A活性的磷酸化状态的影响。我们还将评估CLL的E5-TCL1转基因小鼠模型中的COG112的抗CLL活性。公共卫生相关性：在西方世界的近84,000例白血病中，B细胞慢性淋巴细胞性白血病（B-CLL）最常见，约占所有成人白血病病例的30％。它的特征是单克隆成熟B细胞的无情积累。来自B-CLL患者的肿瘤细胞显示出增加的存活率，这已证明是由于抑制凋亡以及与细胞周期控制和细胞存活有关的基因的改变。在评估在B-CLL细胞中异常激活的信号传导途径时，证明激酶AKT是组成型激活的，AKT的过度刺激导致NFKB途径的激活，从而导致NO和抑制凋亡的产生增加。多年来，鉴于B-CLL的遗传易感性在至少一个具有CLL的一级相对的人中更常见，因此存在B-CLL的遗传易感性。在B-CLL病例中已记录的染色体畸变中，有11Q的缺失，其中包括一部分PPP2R1B基因，该基因编码了蛋白磷酸酶2a（PP2A）的A2恒定调节亚基。 PP2A是一种众所周知的肿瘤抑制剂，由于11Q缺失导致B-CLL细胞中PP2A活性降低而受到抑制。 PP2A在AKT，有丝分裂激活的蛋白激酶（MAPK）P38，JNK和ERK以及核因子KB（通过IKK）中的作用。预计B-CLL细胞中PP2A活性的降低将通过AKT，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果导致异常信号传导。因此，PP2A的药理激活可能为B-CLL疗法的开发提供了一种新颖的方法。 Cognosci在体外和体内开发了具有有效的抗炎活性的新型治疗肽。在机械研究中，我们最近表明，这些肽抑制磷酸化以及包括p38，JNK和ERK MAPK以及IKK，IKB和NFKB在内的重要炎症信号蛋白的伴随激活。通过分析Cognosci化合物的作用机理，我们发现化合物治疗会导致PP2A的激活和信号转导途径的抑制以及细胞因子，INOS及其产物NO的产生。在对患者原代CD19+/CD5+ B-CLL细胞中几种COG化合物进行初步评估时，我们发现，对于正常B-Cells的EC50的EC50，EC50的EC50的EC50高度高，优先且优先为EC50的EC50和EC50的EC50> 20 UM的EC50。我们建议确定COG112处理对B-CLL细胞中关键信号转导蛋白和PP2A活性的磷酸化状态的影响。我们还将评估CLL的E5-TCL1转基因小鼠模型中的COG112的抗CLL活性。