Dr Vasquez on NAPRT as a Potential Biomarker for NAMPT Inhibition in Pediatric Rhabdomyosarcoma

"We performed comprehensive testing of NAPRT at the gene expression level, the methylation level, and the protein level, and found that approximately 30% to 40% of patients also have loss of NAPRT expression. [Based on this, we think that NAPRT expression] could be a viable biomarker for [the efficacy of NAMPT inhibitors] going forward."

Juan Vasquez, MD, an assistant professor of Pediatrics (Hematology/ Oncology) and the associate program director of the Pediatrics Hematology/Oncology Fellowship at Yale School of Medicine, discussed research elucidating the potential predictive utility of NAPRT expression due to tumor-specific promoter CpG island methylation for successful responses to NAMPT inhibition in a subset of patients with pediatric rhabdomyosarcoma.

In a preclinical study, Vasquez and colleagues evaluated the role of NAPRT expression as a potential biomarker of sensitivity to NAMPT inhibitors. Approximately 50% of rhabdomyosarcoma models demonstrated loss of NAPRT expression, which conferred marked sensitivity to NAMPT inhibition, Vasquez began. In vitro, NAPRT-deficient cells exhibited profound cell death upon treatment with NAMPT inhibitors at nanomolar concentrations, whereas NAPRT-expressing cells were resistant, he detailed. Notably, the cytotoxic effect of NAMPT inhibitors in NAPRT-expressing models was reversed with the addition of nicotinic acid, suggesting the salvage pathway mediated by NAPRT functionally protects against NAD+ depletion, Vasquez explained.

This mechanistic relationship was validated in vivo using rhabdomyosarcoma mouse models, Vasquez continued. NAPRT-deficient tumors responded robustly to NAMPT inhibition, whereas co-administration of dietary nicotinic acid reversed this therapeutic effect in NAPRT-expressing models, he reported. These findings supported the hypothesis that NAPRT loss renders rhabdomyosarcoma cells dependent on the NAMPT-mediated salvage pathway for NAD+ synthesis, creating a selective vulnerability to NAMPT inhibition, he said.

To assess the clinical relevance of this biomarker, Vasquez and colleagues partnered with the Children’s Oncology Group to access tumor specimens from 109 pediatric patients with rhabdomyosarcoma previously enrolled on cooperative group trials. Comprehensive profiling of these samples—including gene expression, promoter methylation, and protein analysis—revealed that approximately 30% to 40% of tumors lacked NAPRT expression, Vasquez shared. These data suggest that NAPRT loss may be a clinically relevant biomarker to identify patients who are most likely to benefit from NAMPT-targeted therapies and inform the design of future biomarker-driven clinical trials in pediatric rhabdomyosarcoma, he concluded.