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 癌症治疗的领域正处于令人兴奋的关头。主要进步 了解导致癌症进展和化学抗性的分子缺陷以及 可用的分子靶向药物的急剧增加，提供了前所未有的机会 潜在有用的组合疗法。最近的FDA决定进一步帮助了科学的追求 允许对组合的临床测试涉及多种未经批准的药物。 较新的代理针对控制基因表达的信号传导途径的目标步骤，包括抑制剂 生长因子与其受体和抑制剂的结合，例如酪氨酸激酶抑制剂。更多 RNAi代理的最新引入为基因沉默提供了更多机会。 转录级别。该项目的目的是开发概念（数学框架）和方法 为了组合调节信号级联中不同步骤的代理，目的是实现真实 协同或临床协同作用。我们提出了三个目标，使用wnt/� -catenin/survivin信号作为模型 路径。该途径在癌症的发展和化学上起着多种重要作用。 第一个目的是建立互动药效模型（IPM） 针对转录前和后信号事件。这些模型与单个代理PD一起使用 参数值（斜率，EMAX，EC50，从文献值中选择以及AIM 3中的实验数据）至 模拟不同组合的结果。用在 AIM 2以确定AIM 3中实验验证的协同，加性或拮抗组合。 第二个目的是开发一种具有统计确定性量相互作用的方法 在平行或非平行浓度效应曲线的药物中。第三个目的是获得 模型预测的实验验证。第一个目标是在培养的细胞中获得的PD参数 wnt/�-catenin/survivin的单个代理的值 信号传导（例如，针对卷曲的抗体，siRNAS（染色，pp2a，survivin）和一个小分子 药物OHL（发现可以减少 - 帕宁蛋白/Survivin信号传导）。效果包括野生型遗物 mRNA和蛋白质水平，总和非磷酸化 - 蛋白质和TCF/LEF 转录活动。第二个目标是评估是否实现了模型预测的互动性 体内和体内。 潜在收益是三倍。首先，结果将有助于建立靶向组合 信号通路中的多个步骤。第二，鉴于Wnt/® -Catenin/survivin的关键作用 肿瘤发育中的信号传导将进一步产生其对治疗增长的调制的见解。 第三，克服了Survivin介导的化学抗性，这是治疗失败的主要原因，将改善 化学疗法的效率。