In fall 2016, NCATS issued 11 Therapeutic/Indication Pairing projects. The funded preclinical projects will serve as “use cases” to demonstrate the utility of an independent crowdsourcing effort or a computational algorithm to predict new therapeutic uses of an existing drug or biologic. Learn more about the projects below:
- Anti-Virulence Drug Repurposing Using Structural Systems Pharmacology
- CXCR2 Antagonism in the Immunometabolic Regulation of Type 2 Diabetes
- Drug Repositioning in Diabetic Nephropathy
- Ketorolac and Related NSAIDs for Targeting Rho-Family GTPases in Ovarian Cancer
- Network-Driven Drug Repurposing Approaches to Treat Coronary Artery Disease
- Preclinical Evaluation of a Neutrophil Elastase Inhibitor for the Treatment of Inflammatory Bowel Disease
- Quantum Model Repurposing of Cethromycin for Liver Stage Malaria
- Repurposing Lesogaberan for the Treatment of Type 1 Diabetes
- Repurposing Misoprostol for Clostridium Difficile Colitis as Identified by PheWAS
- Repurposing Pyronaridine as a Treatment for the Ebola Virus
- Therapeutic Repurposing of Benserazide for Colon Cancer
Principal Investigator: Lei Xie, Ph.D.
Grant Number: 1-R21-TR001722-01
The emergence of superbugs that are resistant to antibiotics of last resort poses a serious threat to human health. The repurposing of safe drugs to target bacterial virulence has emerged as an important strategy to combat drug-resistant pathogens. Using mouse models of infection and rigorous statistical analysis, this team will preclinically validate the effectiveness of raloxifene, a drug currently used to prevent osteoporosis and invasive breast cancer in postmenopausal women. The team will also identify potentially more effective drugs approved by the Food and Drug Administration that target the same biological pathway as raloxifene.
Allegheny-Singer Research Institute
Principal Investigator: Nick Giannoukakis, Ph.D.
Grant Number: 1-R21-TR001728-01
This team will conduct a preclinical study of CXCR2 chemokine receptor inhibitor AZD5069 in mouse models of type 2 diabetes characterized by obesity and insulin resistance. The goals of the study are to determine if AZD5069 can improve insulin sensitivity and glucose and insulin tolerance in pre-diabetic mice concurrent with prevention or delay in onset of high blood sugar, improve and stabilize insulin sensitivity in diabetic mice, and preserve and stabilize beta cell function in diabetic mice. This study could establish a novel direction for type 2 diabetes therapy and potentially for other inflammation-associated disorders of metabolism.
University of California, San Francisco
Principal Investigator: Minnie M. Sarwal, M.D., Ph.D.
Grant Number: 1-R21-TR001761-01
This project team has identified potential new therapies for diabetic kidney disease (DKD) among existing therapies approved by the Food and Drug Administration to treat other diseases. The team will test these therapies in preclinical mouse models of DKD. Preclinical validation studies of these therapies will be performed to advance proposed treatments to phase 2a clinical trials in humans.
University of New Mexico Health Sciences Center
Principal Investigator: Angela Wandinger-Ness, Ph.D.
Grant Number: 1-R21-TR001731-01
Ketorolac, a nonsteroidal anti-inflammatory drug (NSAID) approved by the Food and Drug Administration, is normally used for pain relief. Ketorolac has also been shown to improve ovarian and breast cancer patient survival. This project team will develop new evidence in support of phase 2 human clinical trials and regulatory approval of ketorolac as an investigational new drug to treat ovarian cancers.
Icahn School of Medicine at Mount Sinai
Principal Investigators: Chiara Giannarelli, M.D., Ph.D., and Johan M. Bjorkegren, M.D., Ph.D.
Grant Number: 1-R21-TR001739-01
Coronary artery disease (CAD) is the leading cause of mortality and disability worldwide. Even in patients treated with the best standard of care, morbidity and mortality remain high. New strategies that directly target atherosclerosis (hardening of the arteries) — the main cause of CAD — are urgently needed. One innovative approach is to find drugs that target the molecular errors that drive atherosclerosis in the arterial wall. This team will rigorously validate the preclinical effectiveness of drugs already approved by the Food and Drug Administration or compounds ready for phase 2a testing, with the goal of translating the findings into human clinical trials for CAD.
Preclinical Evaluation of a Neutrophil Elastase Inhibitor for the Treatment of Inflammatory Bowel Disease
Beth Israel Deaconess Medical Center
Principal Investigator: Efi G. Kokkotou, M.D., Ph.D., D.Sc.
Grant Number: 1-R21-TR001753-01
An estimated 1.4 million Americans suffer from inflammatory bowel disease (IBD), a chronic, debilitating condition that affects primarily young adults. This team will evaluate a potential treatment for IBD using the neutrophil elastase inhibitor AZD9668. The drug will be tested in mouse models of experimental colitis and in biopsies from patients with IBD with the future goal of reaching the market and addressing an unmet medical need in IBD therapeutics.
Johns Hopkins University
Principal Investigator: David J. Sullivan, M.D.
Grant Number: 1-R21-TR001737-01
This team will conduct a preclinical trial in mice of cethromycin, a drug developed to treat pneumonia, as a treatment for liver-stage malaria caused by Plasmodium vivax/ Plasmodium ovale parasites. The objective of this work is to build a solid evidence base for a phase 2, controlled human malaria infection clinical trial. The potential long-term outcome is a new safe, effective malaria prevention drug and/or a replacement of primaquine as a treatment of dormant liver-stage P. vivax/P. ovale parasites.
University of California, Los Angeles
Principal Investigator: Daniel L. Kaufman, Ph.D.
Grant Number: 1-R21-TR001742-01
Lesogaberan, a drug originally developed to treat gastrointestinal reflux disease, could be a potential treatment for type 1 diabetes. This team will test the hypothesis that lesogaberan therapy alone and, to a greater degree, lesogaberan as part of combination therapy can lead to sustained disease remission in a mouse model of diabetes. This study has the potential to lead to rapid translation into clinical trials with patients.
Vanderbilt University Medical Center
Principal Investigator: David M. Aronoff, M.D.
Grant Number: 1-R21-TR001723-01
The bacterium Clostridium difficile is a major cause of antibiotic-associated diarrhea, a leading infectious disease in U.S. hospitals. C. difficile infection can recur multiple times despite treatment and can be fatal. This team will research a possible new application for misoprostol, a drug approved by the Food and Drug Administration, to treat the bacterium. Preclinical studies will be conducted to define the optimal dose and timing of misoprostol to prevent recurrent C. difficile colitis.
Collaborations Pharmaceuticals, Inc.
Principal Investigators: Sean Ekins, Ph.D., D.Sc., and Robert A. Davey, Ph.D.
Grant Number: 1-R21-TR001718-01
In 2014, the outbreak of the Ebola virus in West Africa highlighted the need for broad-spectrum antiviral drugs for this and other emerging viruses. Several groups have performed high-throughput screening and identified drugs approved by the Food and Drug Administration — including amodiaquine, chloroquine, clomiphene and toremifene — that have been shown to block the growth of the Ebola virus in the laboratory. This study will build upon these screens to characterize the properties of the compound pyronaridine, which is approved in Europe to treat malaria, prior to determining effectiveness in a mouse model of Ebola virus infection.
University of Texas Medical Branch at Galveston
Principal Investigator: Csaba Szabo, M.D., Ph.D.
Grant Number: 1-R21-TR001734-01
Hydrogen sulfide, commonly known as “swamp gas” or “sewer gas,” has been identified as a biological substance produced in colon cancer cells by a protein that, if blocked, causes cancer cells to stop growing. This project team aims to determine whether benserazide, a compound used in the treatment of Parkinson’s disease, may be suitable for repurposing to treat advanced colorectal cancer. The team will evaluate this compound in cell-based models, biochemical assays and animal models of colon cancer.