Zhou Wang, PhD, and Daniel Shevrin, MD

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 5a-reductase inhibition on IAAT using LuCaP35, another AR-positive prostate xenograft tumor model. One difference between LuCaP35 and LNCaP is that the androgen receptor (AR) in LuCaP35 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 LuCaP35 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.

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