Targeting Androgen -IGF Interactions in Prostate Cancer

描述（由申请人提供）：相当大比例的前列腺癌患者接受雄激素剥夺（AD）治疗最终在兰花睾酮水平设置下发展为进行性疾病。已经提出的AD失败的两种机制是1)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)生长因子如胰岛素样生长因子-1 （IGF-1）及其受体IGF-1R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，阻断肾上腺雄激素和IGF-1R将改善患者的临床结果。细胞培养研究表明，小分子中-北二氢石榴酸（NDGA）抑制癌细胞中的IGF-1R。由于该药物在临床前模型中是安全的，因此计划在复发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调节效果。与此同时，将开发一个小鼠模型，其中可以探索雄激素和IGF-1与NDGA靶向AR刺激。携带雄激素反应性LAPC-9人前列腺癌细胞的小鼠将接受AD、NDGA和药物吡格列酮（以减少循环游离IGF配体）的联合治疗。类似地，假设除了用NDGA阻断受体外，还可以通过药理学降低循环IGF水平来减弱前列腺中的IGF- r信号。NDGA单独和联合吡格列酮将在雄激素非依赖型前列腺癌患者中使用标准疗效标准进行II期研究。与这些研究并行，肾上腺雄激素的AR信号将成为目标。酮康唑是一种肾上腺类固醇生物合成抑制剂，是一种广泛使用的减少肾上腺雄激素产生的方法。尽管初始反应高，但大多数患者对该疗法产生耐药性，限制了其长期临床疗效。据推测，酮康唑的抵抗是通过肾上腺增生发生的，这种抵抗可以通过地塞米松抑制促肾上腺皮质激素（ACTH）的分泌来克服。在II期试验中，将测量酮康唑随时间推移对ACTH水平的影响，并测量临床进展时酮康唑联合地塞米松抑制总ACTH的疗效。随后，在这些早期研究的基础上，将尝试与NDGA、吡格列酮、酮康唑和地塞米松联合治疗，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。

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.