Treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (androgen) by surgical and pharmacological castration. Unfortunately, this form of therapy is not curative and eventually the disease will return in a castration resistant form. Once the disease is castration resistant, the survival time is approximately two years before the patient will succumb to his disease. To develop new therapies, a target must be known. Our laboratory identified the N-terminal domain of the androgen receptor as a novel therapeutic target for drug development. This target is supported by data showing that targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified EPI and sintokamide as first in class of antagonists to androgen receptor N-terminal domain. These compounds were both specific and bind to the N-terminal domain of androgen receptor. However, they appear to have different mechanisms of action. Now we draw on this progress and in Aim 1 we propose to characterize the mechanism of sintokamide that causes inhibition of androgen receptor activity.
Aim 2 will determine the molecular mechanisms of androgen-repressed genes to yield clues about potential acquired resistance, possible combination therapies, and pharmacodynamic biomarkers.
Aim 3 will elucidate binding characteristics.
Aim 4 will test combinations of compounds versus monotherapies in vivo using human prostate cancer xenografts. These novel inhibitors to the androgen receptor N-terminal domain are the only ones available for an N- terminal domain of any steroid hormone receptor and represent a new class of androgen receptor antagonists. All data generated will be novel and provide new insight into potential mechanisms of resistance, drug development, and reveal possible pharmacodynamic markers.

Public Health Relevance

Once prostate cancer becomes castration-resistant there are no long-term or curative therapies that can be offered and the patient will succumb to his disease in a few years. There is mounting evidence supporting the concept that development of castration-resistant disease is causally related to molecular changes affecting the androgen receptor that include expression of constitutively active truncated splice variants that lack a C-terminus ligand-binding domain. Here we propose studies to reveal the mechanisms of antagonists of androgen receptor activation function-1 for further development of novel therapeutics that will delay or prevent hormonal progression to the terminal stage of prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Kondapaka, Sudhir B
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V5 4E6
Tien, Amy H; Sadar, Marianne D (2018) Order within a Disordered Structure. Structure 26:4-6
Shimizu, Yasuomi; Tamada, Satoshi; Kato, Minoru et al. (2018) Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy. J Clin Med 7:
Hirayama, Yukiyoshi; Sadar, Marianne D (2018) Does increased expression of glucocorticoid receptor support application of antagonists to this receptor for the treatment of castration resistant prostate cancer? AME Med J 3:
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