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% of people treated with 5-FU exhibit circulating concentrations of the drug within the therapeutic window.

More than 60% 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.