Novel Therapeutics:
Biomarker-Guided NMNAT-2 Inhibition to Induce Proteotoxic Collapse in High-MAR Tumors
W. Lee Kraus, Ph.D.
- Professor and Director, Cecil H. and Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center
- Professor and Vice Chair for Basic Sciences, Department of Obstetrics and Gynecology
- Professor of Pharmacology
- Assistant Director for Basic Science, Simmons Comprehensive Cancer Center.
Many aggressive tumors survive by using a hidden “NAD battery” in the cell cytoplasm that helps them avoid toxic protein build-up. Dr. Kraus’s work shows that the enzyme NMNAT-2 fuels this pathway and enables a chemical tag on ribosomes (called MARylation) that keeps cancer cells stable and growing. In ovarian cancer patient samples, NMNAT-2 and MAR rise together, and high MAR is linked to worse progression-free survival, creating a clear way to select patients. This Discovery Track will develop first-in-class small-molecule NMNAT-2 inhibitors and pair them with MAR/NMNAT-2 assays to identify responders and measure drug effect. The combination of a novel, druggable node and a practical biomarker strategy supports a focused, capital-efficient path toward an investable IND program, starting in biomarker-enriched ovarian cancer and expanding to other pathway-active diseases.
