Project 2 (Goetz)

项目 2（戈茨）

• 批准号: 8744905
• 负责人: JAMES Newell INGLE
• 金额: $ 27.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744905
• 关键词: Address; Animals; Aromatase; Aromatase Inhibitors; Biological Availability; Biopsy; Bone Density; Bone Resorption; Breast Cancer Treatment; Cancer Patient; Cancer Therapy Evaluation Program; Cell model; Cells; Clinic; Clinical; Cytochrome P-450 CYP2D6; Data; Dependence; Dose; Drug Kinetics; Dual-Energy X-Ray Absorptiometry; Enrollment; Enzymes; Epidermal Growth Factor Receptor; Estrogen receptor positive; Exhibits; Exposure to; Frequencies; Genes; Genetic; Growth; Growth Factor; Harvest; Hepatocyte; Hot flushes; Human; Hydrochloride Salt; In Vitro; Letrozole; MCF7 cell; Maximum Tolerated Dose; Metabolic Pathway; Metabolism; Mitogen-Activated Protein Kinases; Modeling; Mus; Oral; Oral Administration; Organ; Osteogenesis; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phase II/III Trial; Plasma; Postmenopause; Premenopause; Preparation; Production; Proliferation Marker; Proteins; Recombinants; Recurrence; Repression; Resistance; Severities; Signal Pathway; Signal Transduction; Tamoxifen; Thick; Toxic effect; Toxicology; Uterus; Woman; X-Ray Computed Tomography; Xenograft Model; base; bone; drug development; estrogenic activity; high risk; hormone therapy; in vivo; malignant breast neoplasm; neoplastic cell; phase 1 study; pre-clinical; response; treatment duration; tumor

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.

他莫昔芬（TAM）仍然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，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，是TAM的抗增殖作用的关键。我们观察到CYP 2D 6活性降低与TAM治疗的乳腺癌复发风险较高相关，因此我们将研究重点放在内昔芬上，为该提案提供了初步数据。在荷瘤动物中，内昔芬上级TAM。此外，我们的体外数据表明，内昔芬可以克服与人表皮生长因子受体2（HER 2）表达相关的TAM抗性，因为内昔芬不像TAM那样刺激ER/HER 2串扰。我们将这些数据提交给NCI，他们决定继续进行内西芬药物开发，包括生产临床级盐酸内西芬和临床前毒理学/药理学以供IND提交。我们的初步数据表明，应解决以下问题：1）负责消除内昔芬的代谢途径是什么，内昔芬相关毒性与TAM相似（例如子宫刺激）？2)内昔芬是否具有类似于或大于芳香酶抑制剂（Al’s）的体内抗肿瘤活性，以及内昔芬是否在对TAM或Al’s具有抗性的细胞中表现出抗肿瘤活性？3)在人类中，我们能否确定内昔芬的耐受剂量及其毒性特征？和，4）通过体内增殖（Ki-67）和生长因子信号传导的减少以及临床反应评估，内昔芬的该可耐受剂量是否具有生物学相关性？为了解决这些问题，我们提出了以下目标。目标1：进一步表征内昔芬的药代动力学、代谢和毒理学;目的2：研究内昔芬的抗肿瘤活性及其与TAM和来曲唑相比在鼠异种移植模型中对细胞信号传导的作用，并描述内昔芬在TAM和来曲唑抗性肿瘤中的抗肿瘤活性;以及目的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），并描述其毒性特征。在此确定之后，我们将招募额外的患者以探索2种不同剂量的内昔芬：a）MTD和B）与1 pM稳态浓度相关的内昔芬剂量。在这些剂量下，我们将检查内昔芬对子宫厚度、潮热频率和严重程度的影响，并进行配对肿瘤活检以确定内昔芬对生长因子信号传导和增殖中重要蛋白质的影响。