Molecular Approach in Predicting 5-Fluorouracil (5-FU) Efficacy

1R01 CA85381 (Robert B. Diasio, MD, PI)

• 07/24/2001-06/30/2007
• NIH/NCI
• The long term objective of this grant is to examine if a pharmacogenomic approach can be used to predict response and/or toxicity in patients with stage III colorectal cancer to the chemotherapy drug 5-FU.

Abstract:

The objective of this new proposal is to elucidate in a clinical protocol setting the predictive value of quantitating critical enzymes in 5-fluorouracil (5-FU) metabolism. Tumor specimens of colorectal cancer patients being treated with 5-FU will be examined to determine whether 5-FU efficacy can be predicted. Initial studies will focus on the value of quantitative assessment of dihydropyrimidine dehydrogenase (DPD), a critical enzyme, which regulates both the availability of 5-FU for metabolism as well as potential resistance at the level of the tumor. Later studies will combine DPD quantitation with measurement of the critical 5-FU target, thymidylate synthase (TS) and other important anabolic enzymes. This should enable a more rational approach for 5-FU chemotherapy in the future and allow patients, who are unlikely to respond to 5-FU chemotherapy, the opportunity to be considered for alternative therapy (e.g., irinotecan, oxaliplatin), thereby avoiding non-effective, but potentially toxic side effects from 5-FU. At the same time, this should provide added impetus to aggressively treat those patients who are predicted to respond to 5-FU. The specific aims, which will focus on colorectal cancer, where 5-FU is typically used as a single agent include: Specific Aim 1: Determine if measurement of intratumor DPD expression can predict response to 5-FU in a prospective clinical study of patients presenting for colorectal cancer surgery who are subsequently treated with 5-FU and leucovorin (a.—determine if intratumor DPD and TS expression levels can be combined to improve prediction of 5-FU response; b.—determine if there is additive predictive value from measuring the expression of other anabolic enzymatic steps); Specific Aim 2: Determine DPD expression in normal tissues (e.g., normal liver, peripheral blood mononuclear cells) and compare with tumor expression levels, tumor response and host toxicity; and Specific Aim 3: Determine DPD expression in paraffin embedded tissue samples and compare to DPD expression in simultaneously collected snap frozen tissue from the same colorectal cancer patients in order to demonstrate the utility of this diagnostic approach. Recently developed quantitative PCR methodology which will allow us to determine expression levels in needle biopsy sized tissue samples coupled with our thorough understanding of 5-FU metabolism provided an opportunity to test this type of pharmacogenomic approach that, if successful, may be extended to other chemotherapeutic agents in the future.