Genetics of chemotherapy response

In this project, my lab is investigating the mechanisms that control the expression of genes that are necessary for metabolizing 5-FU, building on our previous work.

Effective chemotherapy treatments require a balance between anti-tumor activity and excessive off-target toxicity to the host. This therapeutic window between ineffective and toxic drug levels is extremely narrow for most chemotherapeutics.

For instance, recent data suggest that less than 20 percent of people treated with 5-FU exhibit circulating concentrations of the drug within the therapeutic window.

More than 60 percent of people treated with the standard calculated dose of 5-FU experience suboptimal drug exposure levels, which correlates with reduced anti-cancer efficacy.

Earlier studies from my lab provided some of the first evidence that altered regulation of genes in the 5-FU catabolic pathway may contribute to underexposure to 5-FU. In addition, my lab was the first to provide direct evidence that certain genetic variants in the DPD gene increase the degradation of 5-FU to inactive metabolites.