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（AIS）被广泛用作绝经后妇女雌激素受体阳性乳腺癌的辅助治疗。与他莫昔芬（TAM）相比，AIS的毒性等于或更高的疗效和更低的毒性，该药物多年来是选择的药物。 Exemestane（EXE）是第三代AI，在治疗乳腺癌患者中表现出功效，与TAM和其他AI一样，对EXE和EXE的总体反应有很大的个体间差异毒性的发生，但这种可变性的原因尚未阐明。药物代谢的差异可能是患者之间可变性的来源。遗传变异发生在I阶段和II期代谢反应中的几种酶中，其中许多可能导致酶活性的改变，从而改变对药物的治疗反应。 EXE被广泛代谢为未改变的EXE，在尿液中不到1％，等离子体的发现为10％。我们已经表征了EXE代谢途径，并在此过程中确定了最活跃的酶。一个关键的代谢步骤之一是减少17酮组形成17-二氢去甲烷（17-OH-EXE），该代谢物在体外表现出显着的抗芳香族酶活性，并通过udp-glucuroonded在udp-glucuronidad中，由udp-glucuronations（UGTS）在uline中进行了葡萄糖醛酸化。在初步研究中，我们表明，UGT2B17中的缺失多态性可能对EXE在肝脏中的处置产生重大影响，从而有可能对其治疗作用产生重大影响。除了17-OH-EXE及其葡萄糖醛酸酯外，还有其他4种EXE代谢物，其中两个源自17-OH-EXE。在这些研究和以前的研究中，观察到来自不同个体的EXE代谢产物形成的显着差异。这些数据强调了了解遗传变异是否可能影响个人对药物的反应的重要性。我们的假设是，EXE代谢是EXE代谢谱的个体间变异的重要来源，而EXE-Metabolizing酶中的那些多态性则在影响EXE治疗功效和毒性方面起作用。该提案的具体目的是，（1）表征EXE代谢途径，并确定活性酶中功能性多态性在EXE代谢中的体外效应，（2）建立EXE代谢谱分析动力学，并确定在ugt 2b17 deletion exe exe exe exe exe exe exe exe exe exe中是否存在相关性（3代谢酶基因型，血清EXE代谢产物特征以及EXE诱导的毒性和不良事件在大量服用EXE的妇女中，利用NCIC CTG MAP中的临床数据和临床数据。3在化学戒指和风险降低中检查EXE的试验。总之，这些研究将使我们能够充分表征EXE-Anetabolization酶途径中可能在EXE临床效力中重要的Exe-Anetabolization酶途径中的功能性多态性。