P-1: 5A-Reductase Inhibition in Intermittent Androgen Ablation Therapy in Pros

前列腺癌患者接受雄激素消融治疗后不可避免地复发 难治性肿瘤，常有AAT引起的副作用。试图推迟癌症的发生 尼古拉斯·布鲁乔夫斯基博士：向雄激素非依赖性发展并提高生活质量 开发了间歇性雄激素消融疗法(IAAT)。许多前列腺癌患者正在接受治疗 使用IAAT，有时与5a还原酶抑制剂(非那雄胺或度他雄胺)一起使用。然而， IAAT的疗效没有定义，与非那雄胺或度他雄胺相关的生存益处 IAAT中的行政问题尚未得到解决。此外，从非周期转换到周期运行的标准是- IAAT中的周期尚不清楚。在我们患者权益倡导者的支持下，我们决定解决 以上是关于IAAT的问题。我们已经提出了我们的研究假设，即阻断睾丸激素(T) 在非周期(T正在恢复时)用5a-还原酶抑制剂转化二氢睾酮(DHT) 超诱导肿瘤抑制雄激素反应基因并增强IAAT的疗效。近期 使用LNCaP皮下移植瘤模型的初步研究有力地支持了上述观点 假设。在IAAT的非周期给药显著增强了非那雄胺的诱导 肿瘤抑制雄激素反应基因U19，延缓肿瘤生长，延长小鼠生存期 主持人。为了改进IAAT，我们提出了以下四个具体目标： 1.用另一种AR阳性前列腺LuCaP35测定5CT-还原酶抑制对IAAT的影响 异种移植瘤模型。LuCaPSS和LNCaP的一个区别是雄激素受体(AR)在 LuCaPSS是野生型，而LNCaP的AR在配体结合区有突变。 2.确定抑制5a-还原酶是否增强了肿瘤抑制雄激素的表达- LuCaPSS前列腺癌在裸鼠体内IAAT过程中的反应基因 3.在动物模型上观察改变IAAT间期的作用。 4.进行II期临床试验，以验证5a-还原酶在非周期中抑制的假设 IAAT增强前列腺癌细胞雄激素反应基因的表达，前列腺癌是主要终点， 延长血清PSA倍增时间，这是次要终点。 该翻译项目的成功将增强/优化IAAT，并为 第三阶段临床试验，以确定在IAAT中应用度他雄胺是否可以延缓进展到 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.