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.