Treatment for advanced prostate cancer involves the reduction of the patients'levels of testosterone (androgen). Unfortunately, this form of therapy is not curative and eventually the disease will return in a castrate resistant form (also called hormone refractory or androgen-independent). Once the disease is castrate resistant, the survival time is approximately two years before the patient will succumb to his disease. There are not any effective therapies currently available for these patients. To develop new therapies, a target must be known. Our laboratory has 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 the N-terminal domain of the androgen receptor is activated by alternative pathways in the absence of androgens and targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified two structurally unrelated small molecules (EPI-001 and SINT1) isolated from marine sponges that inhibit transactivation of N-terminal domain of the androgen receptor. These small molecules have in vitro (cell culture) and in vivo (animal) specific activity to block proliferation and androgen receptor activity, and decrease tumor burden of castrate-resistant xenografts. Our ultimate goal is to move these compounds, or their structural derivatives, into clinical trials. To meet this goal a number of items need to be fulfilled and several are addressed here.
Specific Aim 1 will synthesize and test single stereoisomers or achiral derivatives of EPI-001 in cell based assays for activity and make a synthetic, and more stable derivative of SINT1.
Specific Aim 2 will delineate the molecular mechanisms involved in EPI-001 and SINT1 inhibition of transactivation of the AR NTD.
Specific Aim 3 will test the efficacy of SINT1 and EPI-001 and various analogues in different models of prostate cancer. While conventional therapy has concentrated on androgen-dependent activation of the androgen receptor through its C-terminal ligand-binding domain, our concept of blocking transactivation of the N-terminal domain of the androgen receptor for the therapy of advanced prostate cancer has not been previously addressed. There are no inhibitors to the N-terminal domain of the androgen receptor and such compounds would represent a new class of antagonists. The capability to inhibit transcriptional activity of the androgen receptor by targeting the N-terminal domain to block tumor growth in the absence of testicular androgen presents a new direction for the development of antagonists to the androgen receptor for the clinical management of prostate cancer.

Public Health Relevance

Once prostate cancer becomes castrate-recurrent there are no effective therapies that can be offered and the patient will succumb to his disease in approximately two years. There is mounting evidence supporting the concept that development of castrate-recurrent disease is causally related to molecular changes affecting the function of the androgen receptor. Here we propose to develop small molecules that target a unique region of the androgen receptor that will delay or prevent hormonal progression to the terminal stage of prostate cancer. Project Narrative Once prostate cancer becomes castrate-recurrent there are no effective therapies that can be offered and the patient will succumb to his disease in approximately two years. There is mounting evidence supporting the concept that development of castrate-recurrent disease is causally related to molecular changes affecting the function of the androgen receptor. Here we propose to develop small molecules that target a unique region of the androgen receptor that will delay or prevent hormonal progression to the terminal stage of prostate cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA105304-10
Application #
8712165
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
British Columbia Cancer Agency
Department
Type
DUNS #
City
Vancouver
State
BC
Country
Canada
Zip Code
V5 1L3
Kato, Minoru; Banuelos, Carmen A; Imamura, Yusuke et al. (2016) Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer. Clin Cancer Res 22:2744-54
Imamura, Yusuke; Tien, Amy H; Pan, Jinhe et al. (2016) An imaging agent to detect androgen receptor and its active splice variants in prostate cancer. JCI Insight 1:
Banuelos, Carmen A; Tavakoli, Iran; Tien, Amy H et al. (2016) Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain. J Biol Chem 291:22231-22243
Yang, Yu Chi; Banuelos, Carmen Adriana; Mawji, Nasrin R et al. (2016) Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer. Clin Cancer Res 22:4466-77
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Myung, Jae-Kyung; Banuelos, Carmen A; Fernandez, Javier Garcia et al. (2013) An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest 123:2948-60
Yang, Yu Chi; Meimetis, Labros G; Tien, Amy H et al. (2013) Spongian diterpenoids inhibit androgen receptor activity. Mol Cancer Ther 12:621-31
Sadar, Marianne D (2012) Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer. World J Urol 30:311-8
Myung, Jae-Kyung; Sadar, Marianne D (2012) Large scale phosphoproteome analysis of LNCaP human prostate cancer cells. Mol Biosyst 8:2174-82

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