Endoxifen as a Novel Hormonal Therapy for Breast Cancer

Endoxifen 作为乳腺癌的新型激素疗法

• 批准号: 8555337
• 负责人: MATTHEW Philip GOETZ
• 金额: $ 28.84万
• 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/8555337
• 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; novel; 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+）的重要药物 乳腺癌。我们已经证明了内昔芬是一种有效的代谢产物，该代谢产生的一部分是细胞色素的 P450 2D6（CYP2D6）代谢，对于TAM的抗增殖作用至关重要。我们的观察 CYP2D6活性的降低与TAM处理的乳腺癌复发风险更高有关 导致我们将研究重点放在内昔芬上，为该提案提供了初步数据。在肿瘤轴承中 动物，内昔芬优于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（HER2）表达相关的TAM抗性，因为 内昔芬不会像Tam那样刺激ER/HER2串扰。我们向NCI提出了这些数据，他们 决定继续进行内氧化氧法药物开发，包括生产临床级内昔芬 盐酸盐和临床前毒理学/药理学，用于IND提交。我们的初步数据表示 应解决以下问题：1）代谢途径是什么负责 消除内昔芬，与内氧蛋白相关的毒性类似于TAM（例如子宫刺激）吗？ 2） 内昔芬的体内抗肿瘤活性相似或大于芳香酶抑制剂（AL），并且DO 内昔芬在抗TAM或Al的细胞中表现出抗肿瘤活性？ 3）在人类中，我们可以确定 可耐受的内昔芬剂量，其毒性特征是什么？并且，4）是这种可耐受剂量的内昔芬在生物学上 相关，通过减少增殖（KI-67）和体内生长因子信号传导评估，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 表征内昔芬的药代动力学，代谢和毒理学；目标2：研究内昔芬抗肿瘤 与TAM相比 letrozole并描述内昔芬在TAM和LETrozole耐药性肿瘤中的抗肿瘤活性；和目标 3：在人类中进行内昔芬的I期研究以确定最大耐受剂量（MTD）和 描述其毒性特征。遵循此确定，我们将招募更多患者探索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， 潮热的频率和严重程度，并进行配对的肿瘤活检以确定内昔芬对 蛋白质在生长因子信号传导和增殖中很重要。