Targeting multiple signaling steps to achieve synergy

针对多个信号步骤以实现协同作用

• 批准号: 8448635
• 负责人: Jessie L.-S. Au
• 金额: $ 36.67万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448635
• 关键词: Antibodies; Binding; Clinical; Combined Modality Therapy; Computer Simulation; Cultured Cells; Data; Defect; Development; Dose; Evaluation; Event; FDA approved; Gene Expression; Gene Silencing; Goals; Growth Factor; In Vitro; Lead; Literature; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Target; Nature; New Agents; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Play; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; RNA Interference; Role; Signal Pathway; Signal Transduction; Simulate; Small Interfering RNA; Solid Neoplasm; Surface; Therapeutic; Thymidylate Synthase; Toxic effect; Treatment Efficacy; Treatment Failure; Tyrosine Kinase Inhibitor; Uncertainty; Up-Regulation; Validation; abstracting; base; cancer therapy; chemotherapeutic agent; chemotherapy; improved; in vivo; inhibitor/antagonist; insight; leukemia; pharmacodynamic model; receptor; research clinical testing; response; small molecule; survivin; tumor; tumor growth; tumor progression

7. Abstract The field of developmental cancer therapeutics is at an exciting juncture. The major advances in the understanding of molecular defects leading to cancer progression and chemoresistance, together with the dramatic increase in the available molecular targeting drugs, provide unprecedented opportunities to develop potentially useful combination therapies. The scientific pursuit is further aided by the recent FDA decision to allow clinical testing of combinations involving more than one unapproved drugs. The newer agents target steps in signaling pathways that control gene expression, including inhibitors of binding of growth factors to their receptors and inhibitors of such as tyrosine kinase inhibitors. The more recent introduction of RNAi agents provides additional opportunity for gene silencing on the post- transcriptional level. The goal of this project is to develop the concept (mathematical framework) and methods for combining agents that modulate different steps in a signaling cascade, with the goal of achieving true synergy or clinical synergy. We propose three aims, using Wnt/¿-catenin/survivin signaling as the model pathway. This pathway plays multiple important roles in cancer development and chemoresistance. The first aim is to establish interactive pharmacodynamic models (IPM) on combinations of agents targeting pre- and the post-transcriptional signaling events. These models are used with the single agent PD parameter values (slope, Emax, EC50, selected from literature values and from experimental data in Aim 3) to simulate the results of different combinations. The in silico results are analyzed with the method developed in Aim 2 to identify synergistic, additive or antagonistic combinations for experimental validation in Aim 3. The second aim is to develop a method that quantifies, with statistical certainty, the interactivity among drugs with parallel or non-parallel concentration-effect curves. The third aim is to obtain experimental validation of model predictions. The first objective is obtain in cultured cells the PD parameter values for single agents directed at several pre- and post-transcriptional steps in Wnt/¿-catenin/survivin signaling (e.g., antibody against Frizzled, siRNAs (against Disheveled, PP2A, survivin), and a small molecule drug OHL (which was found to reduce ¿-catenin/survivin signaling). The effectors include wild type survivin mRNA and protein levels, levels of total and the active non-phosphorylated ¿-catenin, and Tcf/Lef transcriptional activity. The second objective is to evaluate if the model-predicted interactivity is achieved in vitro and in vivo. Potential gains are three-fold. First, the results will assist the development of combinations targeting multiple steps in a signaling pathway. Second, in view of the critical roles of the Wnt/¿-catenin/survivin signaling in tumor development, the results will further yield insights on its modulations for therapeutic gains. Third, overcoming the survivin-mediated chemoresistance, a major cause of treatment failures, will improve the efficacy of chemotherapy.

7. 摘要 发育性癌症治疗领域正处于一个激动人心的时刻。的主要进展 了解导致癌症进展和化疗耐药的分子缺陷，以及 可用分子靶向药物的急剧增加，为开发提供了前所未有的机会 潜在有用的联合疗法。 FDA 最近的决定进一步促进了科学追求 允许对涉及一种以上未经批准的药物的组合进行临床测试。 较新的药物针对控制基因表达的信号通路中的步骤，包括抑制剂 生长因子与其受体和抑制剂例如酪氨酸激酶抑制剂的结合。越多 最近引入的 RNAi 试剂为基因沉默提供了额外的机会。 转录水平。该项目的目标是发展概念（数学框架）和方法 用于组合调节信号级联中不同步骤的代理，以实现真正的目标 协同作用或临床协同作用。我们提出三个目标，使用 Wnt/¿-catenin/survivin 信号传导作为模型 途径。该途径在癌症发展和化疗耐药中发挥着多种重要作用。 第一个目标是建立药物组合的交互式药效模型（IPM） 针对转录前和转录后信号事件。这些模型与单代理 PD 一起使用 参数值（斜率、Emax、EC50，选自文献值和目标 3 中的实验数据） 模拟不同组合的结果。使用 中开发的方法对计算机结果进行分析 目标 2 确定协同、相加或拮抗组合，用于目标 3 中的实验验证。 第二个目标是开发一种方法，以统计确定性量化交互性 具有平行或非平行浓度效应曲线的药物之间。第三个目标是获得 模型预测的实验验证。第一个目标是获得培养细胞中的 PD 参数 针对 Wnt/¿-catenin/survivin 中多个转录前和转录后步骤的单一试剂的值 信号传导（例如，抗 Frizzled 的抗体、siRNA（抗 Disheveled、PP2A、生存素）和小分子 药物 OHL（被发现可以减少 ¿-catenin/survivin 信号传导）。效应子包括野生型生存素 mRNA 和蛋白质水平、总水平和活性非磷酸化 ¿-catenin 水平以及 Tcf/Lef 转录活性。第二个目标是评估模型预测的交互性是否实现 体外和体内。 潜在收益是三倍。首先，结果将有助于组合靶向的开发 信号通路中的多个步骤。其次，鉴于Wnt/¿-catenin/survivin的关键作用 肿瘤发展中的信号传导，这些结果将进一步深入了解其治疗效果的调节。 第三，克服生存素介导的化疗耐药性（治疗失败的主要原因）将改善 化疗的疗效。