Unfortunately, PARPis in preclinical in vivo models and clinical trials in Ewing sarcoma have failed to demonstrate meaningful responses. PARP inhibitors (PARPis) have emerged as an intriguing treatment strategy for patients with Ewing sarcoma, in part because EWS-FLI1 expression confers sensitivity to PARP inhibition. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.Ĭonclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD +, diminished PAR activity, increased DNA damage, and apoptosis. Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD +), a necessary substrate of PARP. Xenograft experiments were performed to determine efficacy and in vivo mechanism. ![]() Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.Įxperimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant.
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