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.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Translational Science
Department
Type
DUNS #
City
State
Country
Zip Code
McKinnon, Timothy; Venier, Rosemarie; Yohe, Marielle et al. (2018) Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma. Oncogene 37:2630-2644
Phelan, James D; Young, Ryan M; Webster, Daniel E et al. (2018) A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature 560:387-391
Lionakis, Michail S; Dunleavy, Kieron; Roschewski, Mark et al. (2017) Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell 31:833-843.e5
Gryder, Berkley E; Yohe, Marielle E; Chou, Hsien-Chao et al. (2017) PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer Discov 7:884-899
Heske, Christine M; Davis, Mindy I; Baumgart, Joshua T et al. (2017) Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma. Clin Cancer Res 23:7301-7311
Guha, Rajarshi; Mathews Griner, Lesley A; Keller, Jonathan M et al. (2016) Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens. J Biomol Screen :
Ceribelli, Michele; Hou, Zhiying Esther; Kelly, Priscilla N et al. (2016) A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell 30:764-778
Ju, Wei; Zhang, Meili; Wilson, Kelli M et al. (2016) Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma. Proc Natl Acad Sci U S A 113:1624-9
Baranello, Laura; Wojtowicz, Damian; Cui, Kairong et al. (2016) RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription. Cell 165:357-71
Chen, Lu; Wilson, Kelli; Goldlust, Ian et al. (2016) mQC: A Heuristic Quality-Control Metric for High-Throughput Drug Combination Screening. Sci Rep 6:37741

Showing the most recent 10 out of 15 publications