Targeting Androgen -IGF Interactions in Prostate Cancer

靶向前列腺癌中雄激素-IGF 的相互作用

• 批准号: 7662286
• 负责人: Charles James Ryan
• 金额: $ 12.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-18 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662286
• 关键词: 2,4-thiazolidinedione; Acids; Adrenal Glands; Androgen Receptor; Androgen Suppression; Androgens; Androstenedione; Attenuated; Cancer Patient; Cell Culture Techniques; Clinical; Clinical effectiveness; Combined Modality Therapy; Data; Dexamethasone; Failure; Goals; Growth Factor; Hormones; Human; IGF1 gene; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Ketoconazole; Ligands; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measures; Mediating; Modeling; Mus; Outcome; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Pioglitazone; Play; Pre-Clinical Model; Production; Progressive Disease; Prostate; Prostatic Neoplasms; Radiosurgery; Receptor Signaling; Relapse; Resistance; Resistance development; Role; SCID Mice; Signal Transduction; Somatomedins; Steroid biosynthesis; System; Testosterone; Thiazolidinediones; Time; Treatment Protocols; adrenal hyperplasia; androgen independent prostate cancer; base; cancer cell; clinical effect; dehydroepiandrosterone; deprivation; experience; improved; inhibitor/antagonist; novel; novel therapeutics; receptor; response; small molecule; therapy resistant; treatment duration; tumor growth

DESCRIPTION (provided by applicant): A significant proportion of patients treated with Androgen deprivation (AD) for prostate cancer ultimately develop progressive disease in the setting of anorchid testosterone levels. 2 mechanisms that have been proposed for the failure of AD are 1) stimulation of the androgen receptor (AR) by the adrenal androgens androstenedione and dehydroepiandrosterone (DHEA) and 2) stimulation of the AR by growth factors such as the insulin like growth factor- type 1 (IGF-1) and its receptor, IGF-1R. Preliminary data suggests that the activity of the IGF axis is partially regulated by androgen. It is hypothesized that blockade of both adrenal androgens and the IGF-1R will improve clinical outcomes in patients. Studies in cell culture indicate that the small molecule meso-nordihydroguariacetic acid (NDGA) inhibits the IGF-1R in cancer cells. Since this agent appears safe in preclinical models, a phase I study in relapsed prostate cancer patients to determine the maximum tolerated dose (MTD) and PSA modulating effects after 28 days of treatment is planned. In parallel with this, a murine model will be developed in which the targeting of AR stimulation by both androgen and IGF-1 with NDGA can be explored. Mice bearing androgen responsive LAPC-9 human prostate cancer cells will be treated with combinations of AD, NDGA and the drug Pioglitazone (to reduce circulating free IGF ligand). Similarly, it is hypothesized that the IGF-R signaling can be attenuated in prostate by pharmacologically reducing circulating IGF levels in addition to receptor blockade with NDGA. Phase II studies of NDGA alone and combined with Pioglitazone will be performed in patients with androgen independent prostate cancer utilizing standard efficacy criteria. In parallel with these studies, AR signaling by the adrenal androgens will be targeted. A widely utilized approach to reducing adrenal androgen production is the use of ketoconazole, an inhibitor of adrenal steroid biosynthesis. Despite high initial responses, resistance to this therapy develops in most patients, limiting its long-term clinical effectiveness. It is hypothesized that resistance to ketoconazole occurs through adrenal hyperplasia, and that this resistance can be overcome by suppressing adrenocorticotripic hormone (ACTH) secretion with dexamethasone. In a phase II trial, the effects of ketoconazole on ACTH levels over time will be measured and the efficacy of combining ketoconazole with total ACTH suppression with dexamethasone at the time of clinical progression will be measured. Subsequently, based on the results of these early studies, attempts will be made at combination therapy with NDGA, Pioglitazone, Ketoconazole and dexamethasone in order to maximally target the interaction of androgen and signaling by the Insulin -like growth factor receptor.

描述（由申请人提供）：相当大比例的前列腺癌雄激素剥夺（AD）治疗患者最终在睾酮水平正常的情况下发展为疾病进展。已经提出的AD失败的2种机制是1）通过肾上腺雄激素雄烯二酮和脱氢表雄酮（DHEA）刺激雄激素受体（AR）和2）通过生长因子如胰岛素样生长因子1型（IGF-1）及其受体IGF-1 R刺激AR。初步数据表明，IGF轴的活性部分受雄激素调节。据推测，肾上腺雄激素和IGF-1 R的阻断将改善患者的临床结局。细胞培养中的研究表明，小分子内消旋去甲二氢胍乙酸（NDGA）抑制癌细胞中的IGF-1 R。由于这种药物在临床前模型中似乎是安全的，因此计划在复发性前列腺癌患者中进行I期研究，以确定治疗28天后的最大耐受剂量（MTD）和PSA调节作用。与此同时，将开发小鼠模型，其中可以探索雄激素和IGF-1与NDGA对AR刺激的靶向作用。携带雄激素响应性LAPC-9人前列腺癌细胞的小鼠将用AD、NDGA和药物吡格列酮的组合治疗（以减少循环游离IGF配体）。类似地，假设除了用NDGA阻断受体之外，IGF-R信号传导还可以通过显著降低循环IGF水平而在前列腺中减弱。采用标准疗效标准，将在雄激素非依赖性前列腺癌患者中开展NDGA单药治疗和与吡格列酮联合治疗的II期研究。在这些研究的同时，将靶向肾上腺雄激素的AR信号传导。一种广泛使用的减少肾上腺雄激素产生的方法是使用酮康唑，一种肾上腺类固醇生物合成的抑制剂。尽管最初的反应很高，但大多数患者对这种疗法产生了耐药性，限制了其长期临床有效性。假设对酮康唑的耐药性通过肾上腺增生发生，并且这种耐药性可以通过用地塞米松抑制促肾上腺皮质激素（ACTH）分泌来克服。在II期试验中，将测量酮康唑对ACTH水平随时间的影响，并测量临床进展时酮康唑与总ACTH抑制剂和地塞米松联合治疗的疗效。随后，基于这些早期研究的结果，将尝试使用NDGA、吡格列酮、酮康唑和地塞米松进行联合治疗，以最大限度地靶向雄激素与胰岛素样生长因子受体信号传导的相互作用。

项目成果

Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF-1 receptor and androgen dependent growth of LAPC-4 prostate cancer cells.

• DOI: 10.1002/pros.20789
• 发表时间: 2008-08-01
• 期刊: The Prostate
• 作者: Ryan CJ;Zavodovskaya M;Youngren JF;Campbell M;Diamond M;Jones J;Shiry L;Allan G;Maddux BA;Goldfine ID
• 通讯作者: Goldfine ID