New paper below [1].
Abstract says little, but addresses a pet peeve of mine.
In the endocrine system, you get a signal intended for a gland somewhere, which will secrete a hormone, destined for a distant location. Implicit is a feedback mechanism to stop the secretion.
The prostate does not participate in the control of testosterone [T] levels. Prior to ADT, T is always available. A common view is that T binds to the androgen receptor [AR] & initiates cell division. This ignores the conversion of T to DHT & the fact that the presence of DHT sets off production of enzymes for its clearance. Hormonal control is local (autocrine) & operates smoothly for decades.
In other words, the AR is not normally involved in some kneejerk response to T. When I see a list of the major changes that occur to the AR as PCa progresses, I see the common responses to androgen deprivation. At diagnosis, the AR itself is mostly normal, while its environment is not.
I have noted that a big early change is the loss of ERbeta & gain of ERalpha estrogen receptors. ERbeta has a growth suppression effect & resists the pro-growth demands of ERalpha. AR has to be brought into play as a partner of ERalpha & this is achieved via coactivators. These have been studied, but BigPharma has its eye only on the AR.
"Steroid receptor coactivators (SRCs)" "are over expressed in a number of cancers such as breast, prostate, endometrial and pancreatic cancers where they promote tumor growth, invasion, metastasis and chemo-resistance."
"... perturbing SRC function with small molecule inhibitors and stimulators has been shown to be effective in reducing tumor growth in vivo. These early studies demonstrate that targeting the SRCs might prove effective for cancer treatment and more effort should be made to realize the untapped potential of developing drugs designed to target these coactivators."
"more effort should be made" Wishful thinking IMO.
...
Coincidentally, two other guys from Baylor had a similar message last year [2].
There is "the need for innovative therapeutic approaches that aim to continue disrupting AR downstream signaling but are orthogonal to directly targeting the AR itself. In this review, we discuss the preclinical research that has been done, as well as clinical trials for prostate cancer, on inhibiting several important families of AR-interacting proteins, including chaperones (such as heat shock protein 90 (HSP90) and FKBP52), pioneer factors (including forkhead box protein A1 (FOXA1) and GATA-2), and AR transcriptional coregulators such as the p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2, SRC-3, as well as lysine deacetylases (KDACs) and lysine acetyltransferases (KATs)."
...
One approach is to target AR coregulators that are corepressors of AR. Paper [3] is titled "Androgen receptor coactivators that inhibit prostate cancer growth."
"Understanding the molecular switches involved in the transition from AR dependent growth promotion to growth suppression and dysregulation of these coactivator proteins promoting androgen-independent invasion may lead to identification of novel therapeutic targets for PCa."
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/283...
Biochem Pharmacol. 2017 Apr 5. pii: S0006-2952(17)30194-6. doi: 10.1016/j.bcp.2017.04.005. [Epub ahead of print]
Steroid receptor coactivators present a unique opportunity for drug development in hormone-dependent cancers.
Rohira AD1, Lonard DM2.
Author information
1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
2
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. Electronic address: dlonard@bcm.edu.
Abstract
Steroid receptor coactivators (SRCs) are essential regulators of nuclear hormone receptor function. SRCs coactivate transcription mediated by hormone stimulation of nuclear receptors and other transcription factors and have essential functions in human physiology and health. The SRCs are over expressed in a number of cancers such as breast, prostate, endometrial and pancreatic cancers where they promote tumor growth, invasion, metastasis and chemo-resistance. With their multiple roles in cancer, the SRCs are promising targets for the development of small molecule agents that can interfere with their function. For instance, perturbing SRC function with small molecule inhibitors and stimulators has been shown to be effective in reducing tumor growth in vivo. These early studies demonstrate that targeting the SRCs might prove effective for cancer treatment and more effort should be made to realize the untapped potential of developing drugs designed to target these coactivators.
Copyright © 2017. Published by Elsevier Inc.
KEYWORDS:
Coregulator; Drug development; Hormone-dependent cancer; Steroid receptor coactivator; Transcription
PMID: 28390937 DOI: 10.1016/j.bcp.2017.04.005
...
[2] ncbi.nlm.nih.gov/pubmed/267...
Horm Cancer. 2016 Apr;7(2):84-103. doi: 10.1007/s12672-015-0239-9. Epub 2016 Jan 4.
Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer.
Foley C1,2, Mitsiades N3,4,5,6.
Author information
1
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Suite R407, MS: BCM187, Houston, TX, 77030, USA.
2
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Suite R407, MS: BCM187, Houston, TX, 77030, USA.
3
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Suite R407, MS: BCM187, Houston, TX, 77030, USA. mitsiade@bcm.edu.
4
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Suite R407, MS: BCM187, Houston, TX, 77030, USA. mitsiade@bcm.edu.
5
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. mitsiade@bcm.edu.
6
Center for Drug Discovery, Baylor College of Medicine, Houston, TX, 77030, USA. mitsiade@bcm.edu.
Abstract
Medical or surgical castration serves as the backbone of systemic therapy for advanced and metastatic prostate cancer, taking advantage of the importance of androgen signaling in this disease. Unfortunately, resistance to castration emerges almost universally. Despite the development and approval of new and more potent androgen synthesis inhibitors and androgen receptor (AR) antagonists, prostate cancers continue to develop resistance to these therapeutics, while often maintaining their dependence on the AR signaling axis. This highlights the need for innovative therapeutic approaches that aim to continue disrupting AR downstream signaling but are orthogonal to directly targeting the AR itself. In this review, we discuss the preclinical research that has been done, as well as clinical trials for prostate cancer, on inhibiting several important families of AR-interacting proteins, including chaperones (such as heat shock protein 90 (HSP90) and FKBP52), pioneer factors (including forkhead box protein A1 (FOXA1) and GATA-2), and AR transcriptional coregulators such as the p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2, SRC-3, as well as lysine deacetylases (KDACs) and lysine acetyltransferases (KATs). Researching the effect of-and developing new therapeutic agents that target-the AR signaling axis is critical to advancing our understanding of prostate cancer biology, to continue to improve treatments for prostate cancer and for overcoming castration resistance.
PMID: 26728473 PMCID: PMC5380740 DOI: 10.1007/s12672-015-0239-9
[Indexed for MEDLINE] Free PMC Article
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[3] ncbi.nlm.nih.gov/pubmed/253...
Am J Clin Exp Urol. 2014 Apr 5;2(1):62-70. eCollection 2014.
Androgen receptor coactivators that inhibit prostate cancer growth.
Daniels G1, Jha R1, Shen Y1, Logan SK2, Lee P3.
Author information
1
Department of Pathology, New York University School of Medicine New York, NY.
2
Department of Pathology, New York University School of Medicine New York, NY ; Department of Urology, New York University School of Medicine New York, NY ; Department of Biochemistry and Clinical Pharmacology, New York University School of Medicine New York, NY.
3
Department of Pathology, New York University School of Medicine New York, NY ; Department of Urology, New York University School of Medicine New York, NY ; Department of New York Harbor Healthcare System, New York University School of Medicine New York, NY.
Abstract
It is well documented that androgen receptor (AR), a steroid hormone receptor, is important for prostate cancer (PCa) growth. Conversely, however, there is increasing evidence that activation of AR by androgens can also lead to growth suppression in prostate cells. AR mediated transcription is regulated by a number of different transcriptional coactivators. Changes in expression level or cellular localization of specific coactivators may play a crucial role in this switch between proliferative and anti- proliferative processes regulated by AR target gene programs. In this review, we discuss the expression and function of several AR coactivators exhibiting growth suppressive function in PCa, including ARA70/ELE1/NCOA4, androgen receptor coactivator p44/MEP50/WDR77, TBLR1, and ART-27. In luciferase reporter assays, they all have been shown to activate AR mediated transcriptional activation. ARA70 exists in two forms, the full length nuclear ARA70α and internally spliced cytoplasmic ARA70β. For p44 and TBLR1, we identified nuclear and cytoplasmic forms with distinct expression and function. In comparison of their expression (ARA70α, p44, TBLR1 and ART-27) in prostate, these coactivators are expressed in the nucleus of benign prostate epithelial cells while they are more predominantly expressed in cytoplasmic form (ARA70β, cytoplasmic p44 and TBLR1) in PCa. Consistent with their nuclear expression in benign prostate, the nuclear form of these coactivators inhibit PCa growth targeting a subset of AR target genes. In contrast, the cytoplasmic versions of these proteins enhance PCa growth and invasion. Interestingly, first characterized as an AR coactivator in luciferase assays, ART-27 functions as corepressor for endogenous AR target genes. Importantly, the growth inhibitions by these nuclear proteins are androgen-dependent processes and the regulation of invasion is androgen-independent. Understanding the molecular switches involved in the transition from AR dependent growth promotion to growth suppression and dysregulation of these coactivator proteins promoting androgen-independent invasion may lead to identification of novel therapeutic targets for PCa.
KEYWORDS:
Androgen receptor; coactivator; growth inhibition; prostate cancer
PMID: 25374906 PMCID: PMC4219292
Free PMC Article
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