Targeting energy metabolism in gliomas by inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate limiting enzyme of NAD salvage pathway

Pratibha Sharma (India)
Vinay Puduvalli, faculty mentor

Background

• Hometown: Kanpur, India
• Degrees received: PhD in neuro-oncology, Indian Institute of Technology Bombay, Mumbai, India

What is the issue or problem addresses in your research?

Gliomas make up ~30% of all brain and CNS tumors and 80% of all malignant brain tumors and are related with dismal outcomes due to limited response to conventional therapy. Strategies that target single signal transduction pathways have failed to improve clinical outcome. NAMPT is rate limiting enzyme for generations of NAD in several cancer cells and known to govern several cytoplasmic, nuclear and mitochondrial metabolic processes. We examined the feasibility of targeting NAMPT against gliomas.

What methodology did you use in your research?

To evaluate the role of NAMPT for glioma, we knocked out NAMPT from glioma cells using CRISPR Cas9 KO. We also utilized western blot, IHC, immunocytochemistry, confocal microscopy, real-time PCR and global metabolomics to evaluate impact of NAMPT inhibition on genes expression and metabolism of glioma cells. To determine the translational potential of NAD targeting, we also examined the effects of NAMPT inhibition on ex-vivo human glioma samples and on mice intracranial glioma xenograft tissues.

What are the purpose/rationale and implications of your research?

NAMPT inhibition potently targeted several patient derived glioma cells and human tissue with genetically heterogeneous background. Given that NAMPT inhibitors are currently in human trials against solid tumors, our pre-clinical results in glioma provides a strong rationale for translating these findings into clinical evaluation against gliomas.