Endoxifen as a Novel Hormonal Therapy for Breast Cancer

他莫昔芬()仍是治疗雌激素受体阳性(ER)的重要药物 乳腺癌。我们已经证明了艾多昔芬，一种有效的代谢物，部分来自细胞色素 P450 2D6(细胞色素P450 2D6)的代谢，是抗增殖作用的关键。据我们观察， 在治疗的乳腺癌患者中，CYP2D6活性降低与更高的复发风险相关 导致我们将研究重点放在艾多昔芬上，为这一提议提供了初步数据。在荷瘤方面 动物方面，依多昔芬优于。此外，我们的体外数据表明，依多昔芬可以克服 耐药与人表皮生长因子受体2的表达 依多昔芬不会像那样刺激ER/HER2串扰。我们将这些数据提交给NCI，他们 决定继续开发艾多昔芬药物，包括生产临床级别的艾多昔芬 供IND提交的盐酸盐和临床前毒理学/药理学。我们的初步数据显示 应解决以下问题：1)哪些代谢途径负责 消除艾多昔芬，以及艾多昔芬相关毒性与相似(如子宫刺激)？2) 依多昔芬在体内的抗肿瘤活性是否与芳香酶抑制剂(Al‘s)相似或更强？ 艾多昔芬在对或艾尔氏耐药的细胞中显示出抗肿瘤活性？3)在人类中，我们能否识别出一种 艾多昔芬的耐受量及其毒性特征？4)这个剂量的艾多昔芬在生物学上是可耐受的吗 相关，通过体内增殖(Ki-67)和生长因子信号的减少以及 临床反应呢？针对这些问题，我们提出了以下目标。目标1：进一步 研究依多昔芬的药代动力学、代谢和毒理学；目的2：研究依多昔芬的抗肿瘤作用 小鼠异种移植模型中的活性及其对细胞信号的影响 并描述依多昔芬对和来曲唑耐药肿瘤的抗肿瘤活性；目的 3：在人体内进行依多昔芬的第一阶段研究，以确定最大耐受量(MTD)，以及 描述其毒性特征。根据这一决定，我们将招募更多的患者来探索2 不同剂量的艾多昔芬：a)MTD和b)与稳态有关的艾多昔芬剂量 下午1点的浓度在这些剂量下，我们将检查依多昔芬对子宫厚度的影响， 潮热的频率和严重程度，并进行成对的肿瘤活检以确定艾多昔芬对 在生长因子信号传递和增殖中起重要作用的蛋白质。

Tamoxifen (TAM) continues to be an important drug for the treatment of estrogen receptor positive (ER+) breast cancer. We have demonstrated that endoxifen, a potent metabolite resulting in part from Cytochrome P450 2D6 (CYP2D6) metabolism, is critical for TAM's antiproliferative effects. Our observation that reductions in CYP2D6 activity were associated with a higher risk of recurrence in TAM-treated breast cancer led us to focus our studies on endoxifen, providing the preliminary data for this proposal. In tumor bearing animals, endoxifen is superior to TAM. Furthermore, our in vitro data indicate that endoxifen can overcome TAM resistance associated with Human Epidermal growth factor Receptor 2 (HER2) expression because endoxifen does not stimulate ER/HER2 cross-talk as TAM does. We presented these data to NCI and they decided to proceed with endoxifen drug development, including production of clinical grade endoxifen hydrochloride and preclinical toxicology/pharmacology for IND submission. Our preliminary data indicate that the following questions should be addressed: 1) What are the metabolic pathways responsible for elimination of endoxifen, and are endoxifen-related toxicities similar to TAM (e.g. uterine stimulation)? 2) Does endoxifen have in vivo anti-tumor activity similar or greater than aromatase inhibitors (Al's) and does endoxifen exhibit anti-tumor activity in cells resistant to TAM or Al's? 3) In humans, can we identify a tolerable endoxifen dose and what is its toxicity profile? and, 4) Is this tolerable dose of endoxifen biologically relevant, as assessed by reductions in proliferation (Ki-67) and growth factor signaling in vivo, as well as clinical responses? To address these questions, we have proposed the following aims. Aim 1: to further characterize the pharmacokinetics, metabolism and toxicology of endoxifen; Aim 2: to study endoxifen antitumor activity and its effects on cell signaling in a murine xenograft model in comparison to TAM and letrozole and to describe the anti-tumor activity of endoxifen in TAM and letrozole resistant tumors; and Aim 3: to conduct a phase I study of endoxifen in humans to determine the maximum tolerated dose (MTD), and describe its toxicity profile. Following this determination, we will enroll additional patients to explore 2 different doses of endoxifen: a) the MTD and b) the endoxifen dose associated with steady state concentrations of 1 pM. At these doses, we will examine the impact of endoxifen on uterine thickness, frequency and severity of hot flashes, and perform paired tumor biopsies to determine endoxifen's effect on proteins important in growth factor signaling and proliferation.