Role of pharmacogenetics on exemestane metabolism and toxicity

药物遗传学对依西美坦代谢和毒性的作用

• 批准号: 8372081
• 负责人: Philip Lazarus
• 金额: $ 52.73万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-09 至 2013-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372081
• 关键词: Accounting; Adjuvant; Adverse event; Affect; Aromatase; Aromatase Inhibitors; Arthralgia; Breast; Breast Cancer Prevention; Breast Cancer Treatment; Cancer Patient; Cell Fraction; Cell Line; Chemoprevention; Chemopreventive Agent; Clinical Data; Clinical Trials; Code; Correlative Study; Data; Development; Double-Blind Method; Enzyme Gene; Enzymes; Estrogen receptor positive; Excretory function; Exemestane; Exhibits; Gene Deletion; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucuronides; Glucuronosyltransferase; Goals; Haplotypes; Hot flushes; Human; In Vitro; Individual; Individual Differences; Kinetics; Lead; Liver; Malignant Neoplasms; Measures; Mediating; Medical center; Medicine; Metabolic; Metabolic Pathway; Metabolism; Multicenter Trials; National Cancer Institute of Canada Clinical Trials Group; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Placebo Control; Placebos; Plasma; Play; Population; Postmenopause; Prevention; Process; Proteins; Randomized; Reaction; Recruitment Activity; Research; Risk; Risk Reduction; Role; Sampling; Serum; Source; Staging; System; Tamoxifen; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Urine; Variant; Woman; clinical efficacy; drug metabolism; enzyme activity; enzyme pathway; genetic profiling; hormone therapy; in vitro activity; in vivo; interest; malignant breast neoplasm; response; standard of care; urinary

DESCRIPTION (provided by applicant): Aromatase inhibitors (AIs) are widely used as adjuvant treatment for estrogen-receptor positive breast cancer in post-menopausal women. AIs have been demonstrated to have equal to or greater efficacy and less toxicity than tamoxifen (TAM), the drug of choice for many years. Exemestane (EXE) is a 3rd-generation AI that has demonstrated efficacy in the treatment of breast cancer patients, and as with TAM and other AIs, there has been considerable inter-individual variability in overall response to EXE and in the occurrence of toxicities, but the causes of this variability have not been elucidated. Differences in drug metabolism can be a source of variability between patients. Genetic variations occur in several of the enzymes involved in phase I and II metabolic reactions and many of these can lead to alterations in enzyme activity which in turn can alter therapeutic response to drugs. EXE is extensively metabolized as unchanged EXE and is found at less than 1% in urine and 10% in plasma. We have characterized the EXE metabolism pathway and have identified the enzymes most active in this process. One of the key metabolic steps is the reduction of the 17-keto group to form 17-dihydroexemestane (17-OH-EXE), a metabolite that exhibits significant anti-aromatase activity in vitro and which is extensively glucuronidated by UDP-glucuronosyltransferases (UGTs) for excretion in the urine. In preliminary studies, we have shown that a deletion polymorphism in UGT2B17 may have a significant impact on the disposition of EXE in liver and thus potentially on its therapeutic effect. In addition to 17-OH-EXE and its glucuronide, there are 4 other metabolites of EXE, two of which are derived from 17-OH-EXE. Considerable variability in EXE metabolite formation from different individuals was observed in these and previous studies. These data underscore the importance of understanding whether genetic variations may affect an individual's response to the drug. It is our hypothesis that EXE metabolism is an important source of the inter-individual variations in EXE metabolic profiles and those polymorphisms in EXE-metabolizing enzymes play a role in affecting EXE therapeutic efficacy and toxicity. The specific aims of this proposal are to, (1) characterize the EXE metabolism pathway and determine the in vitro effect of functional polymorphisms in enzymes active in EXE metabolism, (2) establish EXE metabolism profile kinetics and determine whether correlations exist in vivo between UGT2B17 deletion genotype and urinary EXE metabolite profiles, and (3) determine whether correlations exist between metabolizing enzyme genotypes, serum EXE metabolite profiles and EXE-induced toxicity and adverse events in a large population of women taking EXE, utilizing samples and clinical data from the NCIC CTG MAP.3 trial that is examining EXE in the chemoprevention and risk reduction setting. Together, these studies will allow us to fully characterize functionally-relevan polymorphisms in the EXE-metabolizing enzyme pathway that are potentially important in EXE clinical efficacy. PUBLIC HEALTH RELEVANCE: Exemestane (EXE) is a 3rd-generation aromatase inhibitor that has demonstrated efficacy in the prevention and treatment of breast cancer but exhibits considerable inter-individual variability in overall response and toxicity in EXE-treated patients. While the causes of this variability have not been elucidated, we have identified some of the enzymes important in EXE metabolism and have shown that a deletion polymorphism in the UGT2B17 gene may have a significant impact on the disposition of EXE in liver and thus potentially on its therapeutic effect. The goals of this proposal are to fully characterize the EXE metabolic pathway, examine the functional effects of prevalent polymorphisms that occur in enzymes active against EXE on EXE metabolism, determine whether correlations exist between metabolizing enzyme genotypes and EXE metabolite profiles in vitro and in vivo, and examine the role of metabolizing enzyme genotype on adverse events and clinical efficacy in women taking EXE. Together, these studies will enable us to fully characterize the polymorphisms in the EXE-metabolizing enzyme pathway that are potentially important in overall response to EXE.

描述（由申请人提供）：芳香酶抑制剂（AIs）广泛用于绝经后女性雌激素受体阳性乳腺癌的辅助治疗。AIs已被证明具有与他莫昔芬（TAM）相同或更高的疗效和更小的毒性，他莫昔芬是多年来的首选药物。依西美坦（EXE）是第三代人工智能，已被证明对乳腺癌患者的治疗有效，与TAM和其他人工智能一样，对EXE的总体反应存在相当大的个体间差异