Cancer Prevention Program

Pharmacogenetics of the Folate Pathway

PI: Neli Ulrich PhD

Pharmacogenetics is the study of how inherited genetic variability affects drug response. In the future, we may be able to tailor therapy to help avoid adverse effects and reduce toxicity of drugs. Dr. Ulrich's focus is on cancer chemotherapeutic drugs that target a specific biochemical pathway – the one of the nutrient folate. Folate metabolism is a target for two major drug groups: folate antagonists (e.g., methotrexate) and thymidylate synthase inhibitors (e.g., 5-fluorouracil). These drugs are widely used in cancer chemotherapy, as treatment for rheumatoid arthritis, and for many other conditions. The administration of these drugs in cancer chemotherapy can cause a state of severe folate depletion with sometimes life-threatening toxicities. Some recent studies suggest that inherited variability (polymorphisms) in proteins in folate metabolism may modify the effectiveness and toxicity of these antifolate drugs. This may explain why some patients respond to the drugs and others do not – or why some patients experience side effects and toxicity.

As part of a collaborative study with the FHCRC Clinical Division Dr. Ulrich investigated whether the toxicity of methotrexate differed depending on patients' genotype in an enzyme called 5,10-methylenetetrahydrofolate reductase (MTHFR). This study showed that marrow transplantation patients with decreased MTHFR enzyme activity are at risk of higher methotrexate toxicity, as evidenced by >30% higher oral mucositis scores and delayed platelet recovery (both serious side-effects of the transplantation process). If these results are confirmed, genotyping patients for this common polymorphism may allow tailoring of methotrexate dose or use of alternative regimens based on a patient's inherited capability to process folate. We hope to obtain funding for expanding this research towards investigating polymorphisms in other proteins in folate metabolism and their effect on methotrexate toxicity and effectiveness.