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

基本信息

批准号：
8527745
负责人：
Philip Lazarus
金额：
$ 51.33万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-09 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527745
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

项目摘要

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.

描述（由申请人提供）：芳香酶抑制剂（AI）广泛用作绝经后女性雌激素受体阳性乳腺癌的辅助治疗。 AI 已被证明具有与多年来首选药物他莫昔芬 (TAM) 相同或更高的疗效和更低的毒性。依西美坦 (EXE) 是第三代人工智能，已在乳腺癌患者的治疗中显示出疗效，与 TAM 和其他人工智能一样，对 EXE 的总体反应和治疗效果存在相当大的个体间差异。毒性的发生，但这种变异的原因尚未阐明。药物代谢的差异可能是患者之间差异的根源。参与 I 期和 II 期代谢反应的几种酶会发生遗传变异，其中许多会导致酶活性的改变，进而改变对药物的治疗反应。 EXE 以未变化的 EXE 形式广泛代谢，尿液中的含量低于 1%，血浆中的含量低于 10%。我们已经描述了 EXE 代谢途径的特征，并确定了在此过程中最活跃的酶。关键的代谢步骤之一是 17-酮基团还原形成 17-二氢依西美坦 (17-OH-EXE)，这种代谢物在体外表现出显着的抗芳香酶活性，并被 UDP-葡萄糖醛酸基转移酶 (UGT) 广泛葡萄糖醛酸化）通过尿液排泄。在初步研究中，我们已经表明UGT2B17的缺失多态性可能对EXE在肝脏中的处置产生显着影响，从而可能对其治疗效果产生显着影响。除了17-OH-EXE及其葡萄糖醛酸苷外，EXE还有其他4种代谢物，其中两种来自17-OH-EXE。在这些研究和之前的研究中观察到不同个体的 EXE 代谢物形成存在相当大的差异。这些数据强调了了解遗传变异是否会影响个体对药物反应的重要性。我们假设 EXE 代谢是 EXE 代谢谱个体间差异的重要来源，并且 EXE 代谢酶的多态性在影响 EXE 治疗功效和毒性中发挥作用。该提案的具体目标是，(1) 表征 EXE 代谢途径并确定 EXE 代谢中活性酶的功能多态性的体外影响，(2) 建立 EXE 代谢谱动力学并确定 UGT2B17 之间是否存在体内相关性缺失基因型和尿液 EXE 代谢物谱，(3) 确定代谢酶基因型、血清 EXE 代谢物谱和大群体中 EXE 诱导的毒性和不良事件之间是否存在相关性服用 EXE 的女性，利用 NCIC CTG MAP.3 试验的样本和临床数据，该试验正在化学预防和降低风险环境中检查 EXE。总之，这些研究将使我们能够充分表征 EXE 代谢酶途径中功能相关的多态性，这些多态性对 EXE 临床疗效可能很重要。