Endoxifen as a Novel Hormonal Therapy for Breast Cancer

他莫昔芬（TAM）仍然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，内昔芬，一种有效的代谢产物，部分来自细胞色素， P450 2D 6（CYP 2D 6）代谢对于TAM的抗增殖作用至关重要。我们观察到 CYP 2D 6活性降低与TAM治疗的乳腺癌复发风险增加相关 使我们把研究重点放在内昔芬上，为这一提议提供了初步数据。荷瘤 动物，内昔芬是上级TAM。此外，我们的体外数据表明，内昔芬可以克服 TAM耐药与人表皮生长因子受体2（HER 2）表达相关， 内昔芬不像TAM那样刺激ER/HER 2相互作用。我们将这些数据提交给NCI， 决定继续进行内昔芬药物开发，包括生产临床级内昔芬 盐酸盐和临床前毒理学/药理学。我们的初步数据显示 以下问题应该得到解决：1）什么是代谢途径负责 消除内昔芬，内昔芬相关毒性是否与TAM相似（例如子宫刺激）？（二） 内昔芬是否具有类似于或大于芳香酶抑制剂（A1）的体内抗肿瘤活性， 内昔芬在对TAM或Al's耐药的细胞中表现出抗肿瘤活性？3)在人类中，我们能识别出 内昔芬的耐受剂量及其毒性特征是什么？和，4）内昔芬的生物学耐受剂量 相关，如通过体内增殖（Ki-67）和生长因子信号传导的减少所评估，以及 临床反应？为了解决这些问题，我们提出了以下目标。目标1：进一步 目的2：研究内昔芬的抗肿瘤作用 活性及其对鼠异种移植模型中细胞信号传导的作用，与TAM和 来曲唑，并描述内昔芬在TAM和来曲唑耐药肿瘤中的抗肿瘤活性; 3：进行内昔芬在人体中的I期研究，以确定最大耐受剂量（MTD），以及 描述其毒性特征。确定后，我们将招募更多患者，以探索2 不同剂量的内昔芬：a）MTD和B）与稳态相关的内昔芬剂量 浓度为1 pM。在这些剂量下，我们将检查内昔芬对子宫厚度的影响， 频率和严重程度的潮热，并进行配对肿瘤活检，以确定内昔芬的影响， 在生长因子信号传导和增殖中重要的蛋白质。

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.