Role of pharmacogenetics on exemestane metabolism and toxicity

描述(申请人提供)：芳香酶抑制剂(AIs)被广泛用于绝经后妇女雌激素受体阳性乳腺癌的辅助治疗。人工智能已经被证明与多年来的首选药物他莫昔芬()具有相同或更高的疗效和更低的毒性。依西美坦(EXE)是已被证明在治疗乳腺癌患者中有效的第三代人工智能，与和其他人工智能一样，对EXE的总体反应和在治疗中的个体间差异很大。 毒性的发生，但这种变化的原因尚未阐明。药物代谢的差异可能是患者之间差异的一个来源。参与第一阶段和第二阶段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变化，进而改变对药物的治疗反应。EXE被广泛代谢为未改变的EXE，在尿液中的含量不到1%，在血浆中的含量不到10%。我们已经确定了EXE代谢途径的特征，并确定了在这一过程中最活跃的酶。代谢的关键步骤之一是将17-酮基还原为17-二氢依西美坦(17-OH-EXE)，这是一种在体外表现出显著的抗芳香酶活性的代谢物，它被UDP-葡萄糖醛酸基转移酶(UGT)广泛地葡醛酸化，以便在尿中排泄。在初步研究中，我们已经表明，UGT2B17的缺失多态可能对EXE在肝脏中的处置产生重大影响，从而潜在地影响其治疗效果。除17-OH-EXE及其葡萄糖醛酸化物外，EXE还有4种代谢物，其中2种来源于17-OH-EXE。在这些和以前的研究中，观察到不同个体的EXE代谢物形成的相当大的差异。这些数据强调了了解基因变异是否会影响个体对药物的反应的重要性。我们的假设是EXE代谢是EXE代谢谱个体间差异的重要来源，EXE代谢酶的多态性在影响EXE的疗效和毒性中起作用。这项建议的具体目的是：(1)确定EXE代谢途径的特征，并确定EXE代谢活跃酶的功能多态性的体外效应；(2)建立EXE代谢谱动力学，并确定在体内UGT2B17缺失基因型与尿EXE代谢物谱之间是否存在相关性；以及(3)利用NCIC CTG MAP.3试验的样本和临床数据，确定在化学预防和降低风险的背景下，代谢酶基因型、血清EXE代谢物谱与EXE诱导的毒性和不良事件之间是否存在相关性。总之，这些研究将使我们能够充分描述EXE代谢酶途径中与功能相关的多态性，这些多态性在EXE临床疗效中具有潜在的重要性。

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.