Margaret Black

Biography

Exploiting nucleoside metabolizing enzymes for novel cancer therapies is a major focus of my lab’s research. We are fundamentally interested in the structure to function relationship of enzymes that catalyze the formation of precursors for DNA and RNA and, most notably, also convert nucleoside analogs or prodrugs to cytotoxic compounds. In a process known as suicide gene therapy, a nucleoside metabolizing gene is delivered to a cancer cell followed by administration of the nontoxic prodrug. The gene product (enzyme) converts the prodrug to a cytotoxin, thereby leading to death of the cancer cell. Our approach employs several molecular strategies to generate enzyme variants with improved activities towards the nontoxic prodrugs for use in suicide gene therapy. Biochemical evaluation along with in vitro and in vivo analysis of derived mutants that display enhanced prodrug activation allows the identification of mutants for use in gene therapy for the treatment of cancer. Molecular modeling of the active site of enzymes and their variants has provided further insights on how the enzyme might be altered to improve prodrug activation and therefore enhance tumor ablation for a safer and more effective cancer cure.