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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090386-09
Application #
8375654
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$245,200
Indirect Cost
$38,295
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hung, Michelle E; Leonard, Joshua N (2016) A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery. J Extracell Vesicles 5:31027
Ye, Cong; Geng, Zhe; Dominguez, Donye et al. (2016) Targeting Ornithine Decarboxylase by α-Difluoromethylornithine Inhibits Tumor Growth by Impairing Myeloid-Derived Suppressor Cells. J Immunol 196:915-23
Kregel, Steven; Chen, James L; Tom, Westin et al. (2016) Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer. Oncotarget 7:26259-74
Nyame, Yaw A; Murphy, Adam B; Bowen, Diana K et al. (2016) Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing Radical Prostatectomy. J Clin Oncol 34:1345-9
Pascal, Laura E; Masoodi, Khalid Z; O'Malley, Katherine J et al. (2015) 5α-Reductase inhibition coupled with short off cycles increases survival in the LNCaP xenograft prostate tumor model on intermittent androgen deprivation therapy. J Urol 193:1388-93
Lindholm, Paul F; Sivapurapu, Neela; Jovanovic, Borko et al. (2015) Monocyte-Induced Prostate Cancer Cell Invasion is Mediated by Chemokine ligand 2 and Nuclear Factor-κB Activity. J Clin Cell Immunol 6:
Zhang, Ali; Zhao, Jonathan C; Kim, Jung et al. (2015) LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer. Cell Rep 13:209-21
Hung, Michelle E; Leonard, Joshua N (2015) Stabilization of exosome-targeting peptides via engineered glycosylation. J Biol Chem 290:8166-72
Loeb, Stacy; Sanda, Martin G; Broyles, Dennis L et al. (2015) The prostate health index selectively identifies clinically significant prostate cancer. J Urol 193:1163-9
Jovanovic, Borko D; Subramanian, Hariharan; Helenowski, Irene B et al. (2015) Clinical Trial Laboratory Data Nested With in Subject: Components of Variance, Sample Size and Cost. Biom Biostat Int J 2:

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