The advancement of the Human Genome Project along with the development of new techniques such as gene chips, automated gene-sequencers and real time quantitative PCR (RT -QPCR) have resulted in a rapidly expanding discipline devoted to the study of genetic differences that affect an individual's response to drugs tenned phannacogenomics. The long-term objective of this proposal is to examine if a phannacogenomic approach can be used to predict response and/or toxicity in patients with stage III colorectal cancer to the chemotherapy drug 5-Fluorouracil (5-FU). Initial efforts will follow up on a promising preliminary study in a small population of patients with disseminated colorectal cancer whose tumors were retrospectively examined using RT- PCR. This study suggested that over 90 percent of the responders to 5-FU therapy (with a median survival over 3 times longer than non-responders) could be identified by quantitating the expression levels of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS).
The specific aims of the current application include: Spec.
Aim 1) Determine the role of intratumor DPD and TS expression in predicting response (time to relapse) to 5-FU in a prospective clinical study of patients presenting with stage III disease -subsequent studies will examine the additive value of other critical enzymes in the fluoropyrimidine pathway; Spec.
Aim 2) Determine DPD and TS expression in normal tissues (e.g., normal intestine, liver, peripheral blood mononuclear cells) and compare with tumor expression levels and host toxicity; and Spec.
Aim 3) Determine DPD and TS expression in paraffin embedded tissue samples compared to simultaneously collected snap frozen tissue in order to demonstrate the utility and validate this diagnostic approach in studies of archival tissue. If this pharmacogenomic approach is shown to be feasible with 5-FU, it could then be extended to potentially other cancer chemotherapy agents in the future, making possible alternative therapies tailored to the individual patient.
|Flores, John Paul; Saif, M Wasif (2013) Novel oral taxane therapies: recent Phase I results. Clin Investig (Lond) 3:333-341|
|Soong, R; Shah, N; Salto-Tellez, M et al. (2008) Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol 19:915-9|
|Ezzeldin, Hany H; Lee, Adam M; Mattison, Lori K et al. (2005) Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res 11:8699-705|
|Blanquicett, Carmelo; Johnson, Martin R; Heslin, Marty et al. (2002) Housekeeping gene variability in normal and carcinomatous colorectal and liver tissues: applications in pharmacogenomic gene expression studies. Anal Biochem 303:209-14|
|Blanquicett, Carmelo; Gillespie, G Yancey; Nabors, L Burt et al. (2002) Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. Mol Cancer Ther 1:1139-45|