PAAR Abstract, 2003

Pharmacogenetics of Anticancer Agents Research Group

Goals

We have created a multidisciplinary, collaborative, and comprehensive (albeit decentralized) Group, involving multiple scientists at four institutions (www.pharmacogenetics.org, The PAAR Group interacts weekly via a scientific videoconference, and is governed by an eight member Executive Committee that meets monthly by teleconference.

Our goals are to identify and evaluate polymorphisms in drug metabolizing enzymes, transporters, or targets relevant to anticancer agents; to determine the association between new and previously identified polymorphisms (genotype) and variability in toxicity and/or response to anticancer agents (phenotype); to define the population diversity of polymorphisms of clinical interest; and to create shared resources of value to other Research Groups in the Pharmacogenetic Research Network. The primary approach is "phenotype to genotype," involving careful phenotyping of laboratory and clinical specimens, followed by polymorphism discovery, functional biochemical investigation, and genotype/phenotype association studies. Our mutual interests in topoisomerase inhibitors (e.g. irinotecan and etoposide) have served as the starting point for investigations that build on one another and have focused on patients, anticancer drugs, and pathways of relevance for improving outcome of pediatric and adult cancer.

Progress

As noted above, the PAAR Group (formed in April 2000) has demonstrated that it can work collaboratively across institutional boundaries. The three cores (Liver Tissue, Molecular Genetics, and Lymphoblastoid Cell Line) are extensively used and supported by web-based shared databases developed by PAAR Group bioinformaticists, and support research projects approved by the PAAR Executive Committee. Strong links have been established with the NCI-sponsored cooperative clinical trial groups (CALGB, COG, and ECOG). In addition, the PAAR Group has established collaborations with members of other PGRN Research Groups, including the CREATE, PMT, PAT, COBRA, and PARC groups.

Our published manuscripts (see PGRN publication list) detail our progress in regard to the pharmacogenetics of glucuronosyltransferases, P450 enzymes (and related nuclear hormone receptors), carboxylesterases, ABC transporters, and drug targets, which are all relevant to one or more anticancer agents. In addition, several papers report association studies in patients treated with one or more anticancer agents. Fifty PAAR submissions to PharmGKB are already approved on the public site.

• Our group has been at the forefront of irinotecan clinical pharmacology. We have demonstrated that a common polymorphism in the UGT1A1 promoter is a major determinant of irinotecan toxicity in cancer patients (Iyer, Pharmacogenom J, 2002), and described the haplotype structure of the UGT1A1 promoter (Innocenti, Pharmacogenetics, 2002). We extended our studies to other UGTs, as we characterized the glucuronidation of the epirubicin by UGT2B7 (Innocenti, Drug Metab Disp, 2001), and discovered new polymorphisms in the UGT2B7 regulatory region, which appear to be associated with variability in morphine glucuronidation in postoperative patients (Sawyer, Clin Pharmacol Ther, 2003). We have also characterized the glucuronidation of the novel anticancer drug flavopiridol (Ramirez, Pharm Res, 2002). Irinotecan is activated by carboxylesterases, and we have characterized the hydrolysis of irinotecan by the carboxylesterases HCE1 and HCE2 (Wu, Clin Cancer Res, 2002), and elucidated the promoter structure of HCE2, including the identification of multiple promoters (Wu, Pharmacogenetics, 2003). Irinotecan is a substrate for the BCRP (ABCG2) transporter, and we have identified BCRP allelic variants and established their relationship to its intestinal expression (Zamber, Pharmacogenetics, 2003), which may impact on oral absorption of irinotecan.
• Our group was the first to identify the involvement of CYP3A in the metabolism of the anticancer agent etoposide, and we identified novel functional polymorphisms in CYP3A that form the basis for polymorphic CYP3A5 expression (Lamba, Pharmacogenetics, 2002; Kuehl, Nat Genet, 2001), and link the co-regulation of CYP3A4 and CYP3A5 (Lin, Mol Pharmacol, 2002). We have determined the importance of these CYP3A polymorphisms, which (along with UGT1A1 and other common functional polymorphisms) are predictors of etoposide pharmacokinetic variability among children with leukemia (Kishi, in press). We have also established the relationships of polymorphisms in CYP3A with docetaxel pharmacokinetics and pharmacodynamics in Asian patients with cancer (Goh, J Clin Oncol, 2002).
• We extended this work to the nuclear hormone receptor PXR, which regulates CYP3A expression, identifying novel polymorphisms in PXR and characterizing their functional importance (Zhang, Pharmacogenetics, 2001).
• The most serious adverse effect of etoposide is its ability to induce secondary malignancies, and we have determined the relationships between common, functional polymorphisms in CYP3A4 and CYP3A5, along with NQO1, the G-CSF receptor, and the MLL gene, in patients who did and did not develop drug-induced second malignancies (Echlin-Bell, Hum Genet, 2003; Blanco, Pharmacogenetics, 2002).
• We have identified a unique mechanism of nonsense-mediated decay that is responsible for downregulation of ABCC4 expression among human livers (Lamba, Hum Mol Genet, 2003).
• We have described the population genetics of a microsatellite in intron 1 of EGFR that has been associated with variability in EGFR (an important target of several new anticancer agents) expression (Liu, Clin Cancer Res, 2003).
• Pharmacogenetic studies have been incorporated into the front line treatment protocols for children with acute lymphoblastic leukemia. Studies to date have established that the in vivo changes in gene expression following antimetabolite therapy can discriminate among related treatments, correlate with response, and may relate to germline polymorphisms (Cheok, Nat Genet, 2003).
• We have developed an experimental method for direct molecular determination of haplotypes (McDonald, Pharmacogenetics, 2002).