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令人兴奋的时刻。 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 FDA 最近的决定进一步促进了潜在有用的联合疗法。 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 试剂为后期基因沉默提供了额外的机会。 该项目的目标是开发概念（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 我们使用 Wnt/¿ 提出三个目标。 -连环蛋白/生存素信号传导作为模型 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） 这些模型与单药 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） 使用中开发的方法模拟不同组合的结果。 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 第三个目标是获得具有平行或非平行浓度效应曲线的药物。 模型预测的实验验证第一个目标是在培养细胞中获得PD参数。 针对 Wnt/¿ 中多个转录前和转录后步骤的单一试剂的值-连环蛋白/生存素 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）效应器包括野生型 survivin。 mRNA 和蛋白质水平、总水平和活性非磷酸化水平 ¿ -连环蛋白和 Tcf/Lef 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。 首先，结果将有助于组合靶向的开发。 其次，考虑到 Wnt/¿ 的关键作用。 -连环蛋白/生存素 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。