A better understanding of pharmacogenetic associations is especially important in cancer chemotherapy, as many chemotherapeutic agents have a very narrow therapeutic index. The fluoropyrimidines 5-fluorouracil (5FU) and its oral prodrug capecitabine are among the most frequently used anticancer drugs. Current body surface area (BSA)-based fluoropyrimidine dosing only insufficiently accounts for inter-individual variability in drug exposure, putting susceptible patients at risk of severe and potentially life-threatening toxicity. We have recently shown that genetic variants in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD), encoding the key enzyme in 5FU catabolism, are important predictors of early-onset fluoropyrimidine toxicity, and that genetic variation in a DPYD-regulatory microRNA (miR-27a) modulates toxicity risk in carriers of DPYD risk variants.
In our current research, we focus our studies on the investigation of phenotype-genotype relationships in the fluoropyrimidine metabolism and mechanism of action using metabolic profiling. Using pharmacometabolomics-informed pharmacogenomics, we aim to identify and characterize potential contributors to inter-individual variability in fluoropyrimidine toxicity to further advance our understanding of the underlying mechanisms and improve the identification of patients at risk of potentially life-threatening adverse events from fluoropyrimidine-based chemotherapy.
Pharmacogenomics of immunosuppressants
After solid organ transplantation, patients require a lifelong immunosuppressive therapy to prevent rejection of the transplanted organ. The main challenge of this therapy is the narrow therapeutic margin of immunosuppressive drugs combined with high, and often unpredictable, intra- and inter-individual variability in pharmacokinetics and pharmacodynamics of the drugs. Especially in the beginning of the therapy, this variability may have serious consequences leading to organ rejection or adverse drug events. Since it has been previously shown that genetic variation is an important factor contributing to the variability in response to immunosuppressants, further research in this field may provide new ways to improve the treatment outcome in transplantation patients.
Our aim is to characterize key factors influencing treatment response by using metabolic profiling combined with sequencing and genotyping of target genes involved in the metabolism and action pathways of immunosuppressants. Currently, our work is focused on heart transplant patients and the project is carried out in collaboration with the Department of Cardiology (Inselspital). Ultimately, we aim to identify biomarkers that can be used in pre-treatment screening of patients in order to choose the optimal therapy regimen and the starting doses of the drugs for each patient. Additionally, we aim to develop new assays for quantification of immunosuppressants and their key metabolites in blood that can be used to gain new insights into the pharmacokinetics of the drugs as well as to improve the routine therapeutic drug monitoring of patients.