Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma...

Area of Science:

• Oncology
• Cancer Metabolism

Background:

• Cancer cells exhibit metabolic deregulation, presenting therapeutic vulnerabilities.
• Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for NAD+ synthesis via the salvage pathway.
• NAMPT is essential for cells with high metabolic demands, making it a potential therapeutic target.

Purpose of the Study:

• To investigate NAMPT as a dependency in rhabdomyosarcoma (RMS), a cancer needing new treatments.
• To evaluate the effects of NAMPT inhibition on RMS proliferation and metabolism.
• To assess the in vitro and in vivo impact of NAMPT inhibition on RMS.

Main Methods:

• Pharmacologic NAMPT inhibition using OT-82 was tested on ten RMS cell lines.
• Cell proliferation and death assays were employed.
• NAD+ levels, NAD+-dependent functions, and energy metabolism were measured.
• Orthotopic xenograft models were used to assess in vivo tolerability, efficacy, and drug mechanism.

Main Results:

• OT-82 depleted NAD+ and inhibited RMS cell growth at nanomolar concentrations.
• Impaired glycolysis was observed in all cell lines; some also showed reduced oxidative phosphorylation.
• ATP depletion led to necrotic cell death in most cell lines.
• In vivo models confirmed NAD+ loss and impaired glycolysis, resulting in complete tumor regression with OT-82 treatment.

Conclusions:

• Rhabdomyosarcoma exhibits significant vulnerability to NAMPT inhibition.
• These findings support further clinical investigation of NAMPT inhibitors for RMS treatment.