Juan Vasquez, MD, is an assistant professor of Pediatrics (Hematology/Oncology) and the associate program director of the Pediatrics Hematology/Oncology Fellowship at Yale School of Medicine. 

Dr Vasquez on the Rationale for Investigating NAMPT Inhibition in Rhabdomyosarcoma

“The chemotherapy we’ve been using for rhabdomyosarcoma really hasn't changed in the past several decades; we’re using pretty traditional chemotherapy. There’s a real unmet need to develop new and novel treatments for these patients.”

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 unmet needs for patients with pediatric rhabdomyosarcoma.

Rhabdomyosarcoma is a malignant neoplasm of skeletal muscle lineage, Vasquez began. It is significantly more prevalent in pediatric populations compared with adult populations and represents the most common soft tissue sarcoma in children, he explained. Standard treatment typically involves a multimodal approach, including systemic chemotherapy, radiation therapy, and surgical resection, he said.

Despite these interventions, prognosis remains poor for patients presenting with advanced-stage disease or those with relapsed or refractory rhabdomyosarcoma, with 3-year overall survival rates falling below 30%, according to Vasquez. Furthermore, the chemotherapeutic regimens used for patients with this malignancy have remained largely unchanged over the past several decades, relying on conventional cytotoxic agents, he stated. Consequently, there is a critical unmet need for the development of novel and more effective therapeutic strategies for this patient population, he emphasized.

These unmet needs led to the initiation of a preclinical study investigating NAPRT expression as a potential biomarker of sensitivity of NAMPT inhibitors. In the study, approximately 50% of rhabdomyosarcoma models had loss of NAPRT expression, indicating the potential of their sensitivity to NAMPT inhibition. In vitro models showed that cells without NAPRT expression demonstrated high levels of cell death following treatment with NAMPT inhibitors. However, cells that expressed NAPRT were resistant to NAMPT inhibition.

Furthermore, an in vivo analysis using rhabdomyosarcoma mouse models demonstrated that tumors without NAPRT expression had robust responses to NAMPT inhibition. Additionally, comprehensive profiling of tumor samples from 109 pediatric patients with rhabdomyosarcoma showed that approximately 30% to 40% of these tumors were NAPRT deficient. Therefore, loss of NAPRT may be a clinically relevant biomarker to identify patients who are most likely to benefit from receiving NAMPT-targeted therapy.

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Juan Vasquez, MD, discussed unmet needs for patients with pediatric rhabdomyosarcoma that investigations of NAMPT inhibition may address.

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.

Juan Vasquez, MD, discusses how loss of NAPRT expression may serve as a biomarker for antitumor activity with NAMPT inhibition in rhabdomyosarcoma.

Juan Vasquez, MD

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Dr Vasquez on the Rationale for Investigating NAMPT Inhibition in Rhabdomyosarcoma

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