Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer

确定山竹果中异戊二烯化氧杂蒽酮在增强前列腺癌中雄激素受体全长和变异形式降解中的作用

• 批准号: 10321238
• 负责人: Jeremy James Johnson
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321238
• 关键词: Androgen Antagonists; Androgen Receptor; Animal Model; Automobile Driving; Binding; Castration; Cell Nucleus; Chemicals; Chemoprevention; Clinical Trials; Development; Diagnosis; Dimerization; Dose; Drug Kinetics; Early Diagnosis; Enzymes; Estrogen Antagonists; Evaluation; Evolution; FDA approved; Fostering; Fruit; Future; GRP78 gene; Garcinia mangostana; Goals; Health; In Vitro; Individual; Lead; Length; Malignant neoplasm of prostate; Microsomes; Mission; Molecular; Molecular Chaperones; Mus; Natural Products Chemistry; Nuclear Translocation; Oral Administration; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphotransferases; Prevention; Property; Prostate Cancer therapy; Public Health; RNA Splicing; Research; Resistance; Resistance development; Role; Source; Stanolone; Structure-Activity Relationship; Testing; Therapeutic; Transgenic Animals; United States National Institutes of Health; Variant; Xanthones; Xenograft procedure; abiraterone; androgenic; base; cancer chemoprevention; cancer therapy; castration resistant prostate cancer; dietary; endoplasmic reticulum stress; enzalutamide; improved; in vivo; innovation; malignant breast neoplasm; men; mouse model; novel strategies; prevent; prostate cancer cell; prostate cancer risk; prostate carcinogenesis; receptor function; side effect; small molecule; transgenic adenocarcinoma of mouse prostate; treatment strategy

PROJECT SUMMARY The androgen receptor has been a target of prostate cancer for over 70 years with the evolution of pharmacotherapy ranging from chemical castration, small molecular inhibition of anabolic enzymes, to blockade of dihydrotestosterone. Despite the variety of these approaches none of these approaches are acceptable for long term treatment across the prostate cancer continuum. Our long term goal is to identify dietary and semi- synthetic xanthones that may inspire a new class of compounds as Selective Androgen Receptor Degraders (SARDs) for prevention and/or treatment of prostate cancer including castration resistant prostate cancer. New approaches are needed because FDA approved drugs for prostate cancer including enzalutamide and abiraterone can develop resistance in as little as 3-6 months of therapy initiation. The mangosteen fruit is a rich source of xanthones including α-mangostin, gartanin and others with more than 80 unique xanthones identified. α-Mangostin and gartanin were chosen from 9 xanthones for our preliminary studies to evaluate xanthones as SARDs. Using an approach incorporating natural products chemistry isolation we will create 4 different mangosteen extracts with different xanthones. We will fully characterize these extracts chemically and mechanistically for AR and AR splice variant (i.e. including AR-V7 a marker of resistance) degradation in vitro and in vivo as well as pharmacokinetic properties including dosing parameters, microsome analysis and p450 interactions. Our central hypothesis is that mangosteen derived xanthones are SARDs that bind to the AR preventing the nuclear translocation and dimerization of AR. Additionally, selected xanthones inhibit kinases that have been shown to post-translationally modify AR. This leads to a decrease in proliferation inducing endoplasmic reticulum stress. The chaperone protein BiP, a marker of endoplasmic reticulum stress, is activated and binds AR directly leading to proteolytic degradation of wild type AR and AR-V7 (a splice variant of AR responsible for anti-androgen resistance). Our objective in this proposal is to identify xanthones with the greatest potential for broad application across the prostate carcinogenesis continuum spanning diagnosis to castration resistance prostate cancer similar to anti-estrogens used to treat prostate cancer. Specific Aim 1. Elucidate how α-mangostin and gartanin disrupt the functionality and translocation of the androgen receptor to the nucleus leading to the proteasomal degradation of androgen receptor. Specific Aim 2. Identify the most active mangosteen extract for AR degradation disruption using a xenograft mouse model while characterizing the pharmacokinetic parameters of xanthones. Specific Aim 3. Determine if oral administration of a well-defined mangosteen fruit extract will inhibit the development of LG-PIN to HG-PIN to prostate cancer in TRAMP mice through disruption of AR.

项目摘要 雄激素受体已经成为前列腺癌的靶点超过70年， 药物治疗，包括化学阉割、合成代谢酶的小分子抑制、阻断 双氢睾酮尽管这些方法多种多样，但这些方法中没有一种是可接受的。 前列腺癌的长期治疗。我们的长期目标是确定饮食和半- 合成的氧杂蒽酮可能激发一类新的化合物作为选择性雄激素受体降解剂 本发明提供了用于预防和/或治疗前列腺癌（包括去势抵抗性前列腺癌）的SARD。新 因为FDA批准了用于前列腺癌的药物，包括恩杂鲁胺和 阿比特龙可在治疗开始后的短短3-6个月内产生耐药性。山竹果是一种丰富的 氧杂蒽酮的来源，包括α-mangostin，gartanin和其他，鉴定了80多种独特的氧杂蒽酮。 从9种氧杂蒽酮中选择α-芒果苷和栀子苷进行初步研究，以评价氧杂蒽酮作为 SARS使用方法结合天然产物化学分离，我们将创建4个不同的 山竹提取物与不同的氧杂蒽酮。我们将充分表征这些提取物的化学性质， AR和AR剪接变体（即包括AR-V7抗性标记）体外降解的机制 以及体内和药代动力学特性，包括给药参数、微粒体分析和p450 交互.我们的中心假设是山竹果衍生的氧杂蒽酮是与AR结合的SARD 阻止AR的核转位和二聚化。此外，选择的氧杂蒽酮抑制激酶 已经证明可以在发病后改变AR。这导致细胞增殖诱导因子的减少。 内质网应激伴侣蛋白BiP是内质网应激的标志物， 并直接结合AR，导致野生型AR和AR-V7（AR的剪接变体）的蛋白水解降解 负责抗雄激素抗性）。我们在这个提案中的目标是确定具有最大 广泛应用于前列腺癌发生连续体的潜力，包括诊断和去势 前列腺癌的治疗方法与前列腺癌的治疗方法相似。具体目标1.阐明 α-mangostin和gartanin如何破坏雄激素受体的功能和向细胞核的移位 导致雄激素受体的蛋白酶体降解。具体目标2。找出最活跃的 山竹提取物的AR降解破坏使用异种移植小鼠模型，同时表征 氧杂蒽酮的药代动力学参数。具体目标3。确定是否口服定义明确的 山竹果提取物将抑制TRAMP小鼠中LG-PIN向HG-PIN向前列腺癌的发展 通过破坏AR。