Project 2 (Goetz)

他莫昔芬()仍是治疗雌激素受体阳性(ER+)乳腺癌的重要药物。我们已经证明，依多昔芬是一种有效的代谢物，部分源于细胞色素P450 2D6(细胞色素P450 2D6)的代谢，它是抗增殖作用的关键。我们观察到，在治疗的乳腺癌中，CYP2D6活性的降低与更高的复发风险相关，这使得我们将研究重点放在了Enoxifen上，为这一提议提供了初步数据。在荷瘤动物中，依多昔芬优于。此外，我们的体外数据表明，艾多昔芬可以克服与人表皮生长因子受体2(HER2)表达相关的抵抗，因为艾诺昔芬不像那样刺激ER/HER2串扰。我们将这些数据提交给NCI，他们决定继续进行endoxifen药物开发，包括生产临床级盐酸endoxifen和提交IND的临床前毒理学/药理学。我们的初步数据表明需要解决以下问题：1)负责消除Enoxifen的代谢途径是什么，与Enoxifen相关的毒性是否与相似(如子宫刺激)？2)Enoxifen在体内的抗肿瘤活性是否与芳香化酶抑制剂(Al‘s)相似或更强，Enoxifen是否在对或Al’s耐药的细胞中显示出抗肿瘤活性？3)在人类中，我们能否确定Enoxifen的耐受剂量及其毒性分布？4)根据体内细胞增殖(Ki-67)和生长因子信号的减少以及临床反应的评估，这种可耐受剂量的endoxifen是否具有生物学相关性？针对这些问题，我们提出了以下目标。目的1：进一步研究艾诺昔芬的药代动力学、代谢和毒理学；目的2：以和来曲唑为对照，研究艾诺昔芬在小鼠移植瘤模型中的抗肿瘤活性及其对细胞信号的影响，并研究艾诺昔芬在和来曲唑耐药肿瘤中的抗肿瘤活性；目的3：进行艾诺昔芬在人体内的I期研究，以确定其最大耐受量，并描述其毒性分布。根据这一确定，我们将招募更多的患者来研究2种不同剂量的艾多昔芬：a)MTD和b)与1 pm的稳态浓度相关的艾多昔芬剂量。在这些剂量下，我们将检查Enoxifen对子宫厚度、潮热频率和严重程度的影响，并进行成对的肿瘤活检，以确定Enoxifen对生长因子信号转导和增殖重要蛋白的影响。

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.