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Matrix Combination Screening

Identification of a Synergistic Combination Between PARP Inhibitors and NAMPT Inhibitors in Ewing Sarcoma

Ewing sarcoma is an aggressive cancer of the bones and soft tissues that affects mostly children and teenagers. The long-term survival rate of patients with recurrent or metastatic disease is less than 20 percent. Despite intensive efforts to understand the molecular mechanisms underlying such disease, few therapeutic avenues are currently available.

Scientific Synopsis

The goal of this project is to identify potential targeted therapeutic combinations that could overcome resistance and lead to a durable response. NCATS’ strategy was to screen drugs displaying activity as single agents in a combinatorial format versus a panel of Ewing sarcoma cell lines to identify drug combinations displaying activities higher than those of their respective single agents at similar concentrations.

The results indicate that poly (ADP-ribose) polymerase (PARP) inhibitors synergized with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This result was explained by the observation that the NAMPT enzyme is the rate-limiting enzyme involved in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, a necessary substrate of PARP. Combination of the PARP inhibitor niraparib with the NAMPT inhibitor GNE-618 in vivo resulted in tumor regression, delayed disease progression and increased overall survival. These studies highlight these drugs’ potential as a possible therapeutic option in treating patients with Ewing sarcoma.

Lead Collaborators

Craig J. Thomas, Ph.D., NCATS, NIH
Lee J. Helman, M.D., National Cancer Institute, NIH
Christine M. Heske, M.D., National Cancer Institute, NIH

Publication

Heske CM, Davis MI, Baumgart JT, Wilson K, Gormally MV, Chen L, et al. Matrix screen identifies synergistic combination of PARP inhibitors and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in Ewing sarcoma. Clin Cancer Res. 2017;23;7301-11.

Public Health Impact

This study highlights the potential of the matrix combination screening platform to discover novel drug combinations toward the treatment of Ewing sarcoma. Mechanistic hindsight provided from such studies may lead to the development of a more effective chemotherapeutic regimen.