Targeting Androgen -IGF Interactions in Prostate Cancer

描述(由申请人提供)：相当大一部分因前列腺癌而接受雄激素剥夺(AD)治疗的患者最终会在睾丸激素水平下降的情况下发展为进展性疾病。已提出的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)；2)胰岛素样生长因子-1(IGF-1)及其受体IGF-1R等生长因子刺激AR。初步数据表明，胰岛素样生长因子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，小分子去甲二氢愈创木酸(NDGA)可抑制癌细胞中IGF-1R的表达。由于这种药物在临床前模型中似乎是安全的，计划在复发前列腺癌患者中进行一项I期研究，以确定28天治疗后的最大耐受量(MTD)和PSA调节效果。同时，将建立一种小鼠模型，在该模型中，可以探索雄激素和带有NDGA的IGF-1对AR刺激的靶向性。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(以减少循环中的游离IGF配体)的联合治疗。类似地，假设除了用NDGA阻断受体外，还可以通过药物降低循环中的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的第二阶段研究将利用标准疗效标准在雄激素非依赖性前列腺癌患者中进行。在这些研究的同时，肾上腺雄激素发出的AR信号也将成为靶点。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，这是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，但在大多数患者中对这种疗法产生了耐药性，限制了其长期临床效果。据推测，对酮康唑的耐药性是通过肾上腺增生产生的，这种耐药性可以通过地塞米松抑制肾上腺皮质激素(ACTH)的分泌来克服。在第二阶段试验中，将测量酮康唑随时间对ACTH水平的影响，并将在临床进展时测量酮康唑与地塞米松联合应用完全抑制ACTH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，以最大限度地针对雄激素的相互作用和胰岛素样生长因子受体的信号传递。

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.