HTS enabled examination of drug combinations

NCATS的基质筛选旨在使用一个定量的高通量组合筛选平台来确定用于治疗多种疾病的协同药物组合。定制的信息界面允许轻松识别对抗性、相加性和协同性的结果。我们的方法有助于通过无数的表型分析来可视化效力变化以及药物组合的疗效增强。许多疾病的护理标准，包括多种癌症的治疗，都涉及药物组合。药物方案可以由多达五种或更多的药物组成，例如R-CHOP(利妥昔单抗、环磷酰胺、羟基柔红霉素、阿霉素、长春新碱和泼尼松)，它通常用于治疗非霍奇金淋巴瘤。这些疗法中的许多都是长期艰苦的临床试验和错误的结果。以这种方式确定临床上有用的联合疗法是站不住脚的，迫切需要在临床前环境中发现可翻译的药物组合的方法。因此，NCATS的研究人员已经建立了一个高通量的药物组合分析平台。这些研究的结果既包括基础研究发现(不同信号通路之间的新相互作用)，也包括转化性发现(发现用于临床评估的新药组合)。重点项目包括： -确定在B细胞驱动的癌症中放大伊布鲁替尼作用的药物； -评价治疗疟疾的组合药物前景； -确定与人类IL-2依赖的成人T细胞白血病的JAK抑制剂结合的药物； -基于免疫毒素的药物组合，用于治疗上皮性癌和血液病； -抗击埃博拉的药物组合。

Matrix screening at NCATS aims to identify synergistic drug combinations for the treatment of multiple diseases using a quantitative high-throughput combinatorial screening platform. A customized informatics interface allows for the facile identification of antagonistic, additive and synergistic outcomes. Our approach facilitates the visualization of potency shifts, as well as efficacy enhancements for drugs in combination across a myriad of phenotypic assays. The standards of care for many diseases, including therapies for multiple types of cancer, involve drug combinations. Drug regimens can be comprised of as many as five or more agents such as R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin doxorubicin, oncovin vincristine, and prednisone) which is commonly used for the treatment of non-Hodgkins lymphomas. Many of these therapies are the result of long and painstaking clinical trial-and-error. The identification of clinically useful combination therapies in this way is untenable and methods to discover translatable drug combinations in pre-clinical settings are urgently needed. NCATS researchers have, therefore, established a high-throughput platform for analyzing drugs in combination. The outcomes of these studies include both basic research discoveries (novel interactions between diverse signaling pathways) and translational (discovery of new drug combinations for clinical evaluation). Highlighted projects include: -Identification of drugs that amplify the actions of ibrutinib in B-cell driven cancers; -Evaluation of the combinatorial drug landscape for malaria; -Identification of drugs that combine with Jak inhibitors in human IL-2 dependent adult T-cell leukemia; -Immunotoxin-based drug combinations for the treatment of epithelial and hematologic cancers; -Drug combinations for combating Ebola.