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Molecular Targets for Castration-Resistant Prostate Cancer
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Molecular Targets for Castration-Resistant Prostate Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 16697

Special Issue Editor

Prof. Dr. Chendil Damodaran

E-Mail Website
Guest Editor
Professor and Director of Urologic Research, University of Louisville, Louisville, KY, USA
Interests: chemoprevention; small molecule discovery; signal transduction; urogenital cancers

Special Issue Information

Dear Colleagues, 

Androgen receptor (AR) signaling plays a key role in prostate cancer (CaP) pathogenesis. While advanced CaP is initially responsive to androgen deprivation therapy (ADT), tumor recurrence occurs frequently, eventually leading to the progression of castration-resistant prostate cancer (CRPC). As the primary driver of CRPC, AR is not only hypersensitive to low levels of androgens and anti-androgens, but it also induces signals through other stimuli. Moreover, the emergence of AR splice variants (AR-SVs) that lack the ligand-binding domain (LBD) also contributes to abiraterone and enzalutamide resistant CRPC. 

This Special Issue discusses innovative approaches in both basic science and translational research as well as clinical evidence to provide a comprehensive overview of the role of AR-dependent and - independent molecular pathways and AR-SVs in CRPC, as well as new advances in the development of targeted therapies for CRPC. Understanding the molecular intricacies of AR-dependent and - independent pathways involved in CRPC progression will aid in the development of better targeted therapies that can be translated to clinics.

Prof. Dr. Chendil Damodaran
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (4 papers)

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Research

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10 pages, 1573 KiB  
Article
Development of Novel Inhibitors Targeting the D-Box of the DNA Binding Domain of Androgen Receptor
by Mariia Radaeva, Fuqiang Ban, Fan Zhang, Eric LeBlanc, Nada Lallous, Paul S. Rennie, Martin E. Gleave and Artem Cherkasov
Int. J. Mol. Sci. 2021, 22(5), 2493; https://doi.org/10.3390/ijms22052493 - 2 Mar 2021
Cited by 19 | Viewed by 4106
Abstract
The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the [...] Read more.
The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR. Full article
(This article belongs to the Special Issue Molecular Targets for Castration-Resistant Prostate Cancer)
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18 pages, 12863 KiB  
Article
Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer
by Izhar Singh Batth, Shih-Bo Huang, Michelle Villarreal, Jingjing Gong, Divya Chakravarthy, Brian Keppler, Sridharan Jayamohan, Pawel Osmulski, Jianping Xie, Paul Rivas, Roble Bedolla, Michael A. Liss, I-Tien Yeh, Robert Reddick, Hiroshi Miyamoto, Rita Ghosh and Addanki P. Kumar
Int. J. Mol. Sci. 2021, 22(4), 1852; https://doi.org/10.3390/ijms22041852 - 12 Feb 2021
Cited by 7 | Viewed by 3119
Abstract
2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as [...] Read more.
2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer. Full article
(This article belongs to the Special Issue Molecular Targets for Castration-Resistant Prostate Cancer)
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16 pages, 4913 KiB  
Article
Androgen Deprivation Induces Transcriptional Reprogramming in Prostate Cancer Cells to Develop Stem Cell-Like Characteristics
by Shiv Verma, Eswar Shankar, F. Naz Cemre Kalayci, Amrita Mukunda, Malek Alassfar, Vaibhav Singh, E. Ricky Chan, Gregory T. MacLennan and Sanjay Gupta
Int. J. Mol. Sci. 2020, 21(24), 9568; https://doi.org/10.3390/ijms21249568 - 16 Dec 2020
Cited by 27 | Viewed by 3614
Abstract
Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic [...] Read more.
Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance. Full article
(This article belongs to the Special Issue Molecular Targets for Castration-Resistant Prostate Cancer)
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Review

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20 pages, 4844 KiB  
Review
An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer
by Michael L. Mohler, Arunima Sikdar, Suriyan Ponnusamy, Dong-Jin Hwang, Yali He, Duane D. Miller and Ramesh Narayanan
Int. J. Mol. Sci. 2021, 22(4), 2124; https://doi.org/10.3390/ijms22042124 - 20 Feb 2021
Cited by 38 | Viewed by 5410
Abstract
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the [...] Read more.
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC. Full article
(This article belongs to the Special Issue Molecular Targets for Castration-Resistant Prostate Cancer)
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