HTS enabled examination of drug combinations

Abstract public domain (NIH RePORTER)

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 Rhabdomyosarcoma -Identification of drugs that combine with FLT3 inhibitors in AML -Survey of the combination drug landscape in pancreatic cancer