5-Alpha-Reductase Inhibition in Intermittent Androgen Ablation Therapy in Prostat

接受雄激素消融治疗（AAT）的前列腺癌患者不可避免地复发雄激素 难治性肿瘤并且经常遭受由AAT引起的副作用。为了延缓癌症 进展到雄激素独立和提高生活质量，博士尼古拉斯Bruchovsky 开发间歇性雄激素消融治疗（IAAT）。许多前列腺癌患者正在接受治疗 与IAAT，有时与5 α-还原酶抑制剂（非那雄胺或度他雄胺）一起使用。但 IAAT的疗效尚未确定，生存益处与非那雄胺或度他雄胺相关 在内部审计和调查小组的行政管理问题上没有得到解决。此外，从关断周期切换到接通周期的标准- IAAT的周期不清楚。在我们的患者倡导成员的支持下，我们决定解决 以上是关于IAAT的问题。我们已经发展了我们的研究假设，阻断睾酮（T） 在关闭周期期间（T恢复时），通过5 α-还原酶抑制剂转化为二氢睾酮（DHT） 超诱导肿瘤抑制雄激素反应基因并增强IAAT的功效。最近 使用皮下LNCaP异种移植肿瘤模型的初步研究强烈支持上述结果 假说.在IAAT的非周期期间给予非那普德显著增强了 肿瘤抑制性雄激素反应基因U19，延缓肿瘤生长，并延长生存期。 主持人为改善内部评核测试，我们建议以下四个具体目标： 1.使用LuCaP 35（另一种AR阳性前列腺）确定5ct-还原酶抑制对IAAT的影响 异种移植肿瘤模型。LuCaPSS和LNCaP之间的一个差异是，在LNCaP中的雄激素受体（AR）是一种高表达的受体。 LuCaPSS是野生型，而LNCaP中的AR在配体结合结构域中具有突变。 2.确定5 α-还原酶抑制是否增强肿瘤抑制性雄激素的表达- 在裸鼠中IAAT期间LuCaPSS前列腺肿瘤再生长中的应答基因。 3.在动物模型中确定改变IAAT的关闭周期间隔的影响。 4.进行II期临床试验，以检验以下假设，即： IAAT增强前列腺癌细胞中雄激素反应基因的表达，这是主要终点， 血清PSA倍增时间，次要终点。 这一转化项目的成功将增强/优化内部审计和评估小组，并为 III期临床试验，以确定度他雄胺在IAAT中的给药是否可以延迟进展， 雄激素非依赖性和延长转移性前列腺癌患者的生存期。

Prostate cancer patients treated with androgen ablation therapy (AAT) inevitably relapse with androgen refractory tumors and often suffer from side effects caused by AAT. In an attempt to delay cancer progression to androgen-independence and to improve the quality of life, Dr. Nicholas Bruchovsky developed intermittent androgen ablation therapy (IAAT). Many prostate cancer patients are being treated with IAAT, sometimes together with a 5a-reductase inhibitor (finasteride or dutasteride). However, the efficacy of IAAT is not defined, and the survival benefits associated with finasteride or dutasteride administration in IAAT have not been addressed. Furthermore, the criteria for switching from off-cycle to on- cycle in IAAT are not clear. With the support of our patient advocacy members, we decided to address the above questions regarding IAAT. We have developed our research hypothesis that blocking testosterone (T) to dihydrotestosterone (DHT) conversion by 5a-reductase inhibitor during the off-cycle (when T is recovering) supra-induces tumor-suppressive androgen-response genes and enhances the efficacy of IAAT. Recent preliminary studies using a subcutaneous LNCaP xenograft tumor model strongly support the above hypothesis. Administration of finasteride during the off-cycle in IAAT significantly enhanced the induction of tumor suppressive androgen-response gene U19, retarded the tumor growth, and prolonged the survival of the host. To improve IAAT, we propose following four Specific Aims: 1. Determine the effect of 5ct-reductase inhibition on IAAT using LuCaP35, another AR-positive prostate xenograft tumor model. One difference between LuCaPSS and LNCaP is that the androgen receptor (AR) in LuCaPSS is wild-type, whereas the AR in LNCaP has a mutation in the ligand-binding domain. 2. Determine whether 5a-reductase inhibition enhances the expression of tumor-suppressive androgen- responsive genes in LuCaPSS prostate tumor regrowth during IAAT in nude mice. 3. Determine the effect of altering the interval of off-cycle in IAAT in animal models. 4. Conduct a phase II clinical trial to test the hypothesis that 5a-reductase inhibition during the off-cycle of IAAT enhances androgen-response gene expression in prostate cancer cells, the primary endpoint, and prolongs serum PSA doubling time, a secondary endpoint. The success of this translational project will enhance/optimize IAAT and provide a strong rationale for a phase III clinical trial to determine if dutasteride administration in IAAT can delay the progression to androgen-independence and prolong the survival of patients with metastatic prostate cancer.