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.
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.
|Ito, Yusuke; Sadar, Marianne D (2018) Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens. Res Rep Urol 10:23-32|
|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:|
|Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H L et al. (2017) Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer. PLoS One 12:e0174134|
|Leung, Jacky K; Sadar, Marianne D (2017) Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Front Endocrinol (Lausanne) 8:2|
|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|
|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|
|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|
|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:|
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