BioCentury
ARTICLE | Distillery Therapeutics

Blocking the NAD+ biosynthesis enzyme NamPRT for PPM1D-mutant tumors

September 19, 2019 7:32 PM UTC

INDICATION: Brain cancer; sarcoma; breast cancer

Inhibiting NamPRT, a nicotinamide adenine dinucleotide (NAD+) biosynthesis enzyme, could treat PPM1D-mutant cancers including glioma, osteosarcoma and breast cancer. In tumor biopsies from glioma patients, high expression of the oncogene PPM1D correlated with low NamPRT expression; and PPM1D-mutant samples had lower NamPRT mRNA levels than wild-type PPM1D samples.The team identified a NamPRT inhibitor tool compound using a screen for synthetic lethal interactions in human astrocytes engineered to harbor PPM1D truncation mutations. Osteosarcoma and breast cancer cell lines with PPM1D mutations had comparable sensitivity to the NamPRT inhibitor. Furthermore, the NamPRT inhibitor reduced tumor burden in xenograft mouse models of PPM1D-mutant glioma and osteosarcoma. Next steps include identifying NamPRT inhibitors that can penetrate the CNS and developing alternate CNS delivery mechanisms...