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Article ; Online: Alternative splicing in prostate cancer progression and therapeutic resistance.

Rawat, Chitra / Heemers, Hannelore V

2024

Abstract: Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to the standard of care treatments for metastatic disease. Recently, alternative ... ...

Abstract	Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to the standard of care treatments for metastatic disease. Recently, alternative splicing has been recognized as a hallmark of CaP aggressiveness. Alternative splicing events cause treatment resistance and aggressive CaP behavior and are determinants of the emergence of the two major types of late-stage treatment-resistant CaP, namely castration-resistant CaP (CRPC) and neuroendocrine CaP (NEPC). Here, we review recent multi-omics data that are uncovering the complicated landscape of alternative splicing events during CaP progression and the impact that different gene transcript isoforms can have on CaP cell biology and behavior. We discuss renewed insights in the molecular machinery by which alternative splicing occurs and contributes to the failure of systemic CaP therapies. The potential for alternative splicing events to serve as diagnostic markers and/or therapeutic targets is explored. We conclude by considering current challenges and promises associated with splicing-modulating therapies, and their potential for clinical translation into CaP patient care.
Language	English
Publishing date	2024-04-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-024-03036-x
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Zs.A 2218: Show issues

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Article ; Online: Deregulated kinase action in prostate cancer: molecular basis and therapeutic implications.

Singh, Nidhi / Heemers, Hannelore V

Endocrine-related cancer

2023 Volume 30, Issue 9

Abstract: Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments ... ...

Abstract	Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments induce remissions but do not cure CaP. Novel and functionally diverse therapeutic targets that control the cell biology that drives aggressive CaP progression are needed to overcome treatment resistance. Because signal transduction that mediates CaP cell behavior is tightly regulated by phosphorylation, kinases have attracted interest as alternative targets for CaP treatments. Here, we examine emerging evidence from recent NextGen sequencing and (phospho) proteomics analyses on clinical CaP specimens that were obtained during lethal disease progression to determine the role of deregulated kinase action in CaP growth, treatment resistance, and recurrence. We provide an overview of kinases that are impacted by gene amplification, gene deletion or somatic mutations during the progression from localized treatment-naïve CaP to metastatic castration-resistant CaP or neuroendocrine CaP, and the potential impact of such alterations on aggressive CaP behavior and treatment efficacy. Furthermore, we review knowledge on alterations in the phosphoproteome that occur during the progression to treatment-resistant CaP, the molecular mechanisms in the control of these changes, and the signal transduction associated with them. Finally, we discuss kinase inhibitors under evaluation in CaP clinical trials and the potential, challenges, and limitations to moving knowledge on the CaP kinome forward to new therapeutic strategies.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Phosphorylation ; Androgen Antagonists/therapeutic use ; Signal Transduction ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Receptors, Androgen/metabolism
Chemical Substances	Androgen Antagonists ; Receptors, Androgen
Language	English
Publishing date	2023-07-26
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-23-0011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4192: Show issues

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Article ; Online: Analyzing the Androgen Receptor Interactome in Prostate Cancer: Implications for Therapeutic Intervention.

Dahiya, Ujjwal R / Heemers, Hannelore V

Cells

2022 Volume 11, Issue 6

Abstract: The androgen receptor (AR) is a member of the ligand-activated nuclear receptor family of transcription factors. AR's transactivation activity is turned on by the binding of androgens, the male sex steroid hormones. AR is critical for the development and ...

Abstract	The androgen receptor (AR) is a member of the ligand-activated nuclear receptor family of transcription factors. AR's transactivation activity is turned on by the binding of androgens, the male sex steroid hormones. AR is critical for the development and maintenance of the male phenotype but has been recognized to also play an important role in human diseases. Most notably, AR is a major driver of prostate cancer (CaP) progression, which remains the second leading cause of cancer deaths in American men. Androgen deprivation therapies (ADTs) that interfere with interactions between AR and its activating androgen ligands have been the mainstay for treatment of metastatic CaP. Although ADTs are effective and induce remissions, eventually they fail, while the growth of the majority of ADT-resistant CaPs remains under AR's control. Alternative approaches to inhibit AR activity and bypass resistance to ADT are being sought, such as preventing the interaction between AR and its cofactors and coregulators that is needed to execute AR-dependent transcription. For such strategies to be efficient, the 3D conformation of AR complexes needs to be well-understood and AR-regulator interaction sites resolved. Here, we review current insights into these 3D structures and the protein interaction sites in AR transcriptional complexes. We focus on methods and technological approaches used to identify AR interactors and discuss challenges and limitations that need to be overcome for efficient therapeutic AR complex disruption.
MeSH term(s)	Androgen Antagonists/therapeutic use ; Androgens/metabolism ; Humans ; Male ; Prostatic Neoplasms/pathology ; Receptors, Androgen/metabolism ; Signal Transduction/genetics
Chemical Substances	Androgen Antagonists ; Androgens ; Receptors, Androgen
Language	English
Publishing date	2022-03-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11060936
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Treatment-induced Treatment Sensitization in Metastatic Castration-resistant Prostate Cancer.

Gupta, Shilpa / Heemers, Hannelore V

European urology

2021 Volume 79, Issue 6, Page(s) 734–735

MeSH term(s)	Humans ; Male ; Prostatic Neoplasms, Castration-Resistant/drug therapy
Language	English
Publishing date	2021-02-16
Publishing country	Switzerland
Document type	Editorial ; Comment
ZDB-ID	193790-x
ISSN	1873-7560 ; 1421-993X ; 0302-2838
ISSN (online)	1873-7560 ; 1421-993X
ISSN	0302-2838
DOI	10.1016/j.eururo.2021.02.004
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Zs.A 1247: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 294: Show issues

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Article: Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer.

Chauhan, Gaurav / Heemers, Hannelore V

Cancers

2021 Volume 13, Issue 16

Abstract: Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies ... ...

Abstract	Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR's transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.
Language	English
Publishing date	2021-08-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13163947
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: PAM50 and Beyond: When Will Tissue Transcriptomics Guide Clinical Decision-making?

Haywood, Samuel C / Gupta, Shilpa / Heemers, Hannelore V

European urology focus

2022 Volume 8, Issue 4, Page(s) 916–918

Abstract: Emerging transcriptomics-based classifiers show promise as biomarkers to guide clinical decision-making in prostate cancer, but require further research, optimization, and validation. ...

Abstract	Emerging transcriptomics-based classifiers show promise as biomarkers to guide clinical decision-making in prostate cancer, but require further research, optimization, and validation.
MeSH term(s)	Biomarkers, Tumor/genetics ; Clinical Decision-Making ; Humans ; Male ; Prognosis ; Prostatic Neoplasms/genetics ; Transcriptome/genetics
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-08-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2405-4569
ISSN (online)	2405-4569
DOI	10.1016/j.euf.2022.08.010
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Analyzing the Androgen Receptor Interactome in Prostate Cancer

Ujjwal R. Dahiya / Hannelore V. Heemers

Cells, Vol 11, Iss 936, p

Implications for Therapeutic Intervention

2022 Volume 936

Abstract: The androgen receptor (AR) is a member of the ligand-activated nuclear receptor family of transcription factors. AR’s transactivation activity is turned on by the binding of androgens, the male sex steroid hormones. AR is critical for the development and ...

Abstract	The androgen receptor (AR) is a member of the ligand-activated nuclear receptor family of transcription factors. AR’s transactivation activity is turned on by the binding of androgens, the male sex steroid hormones. AR is critical for the development and maintenance of the male phenotype but has been recognized to also play an important role in human diseases. Most notably, AR is a major driver of prostate cancer (CaP) progression, which remains the second leading cause of cancer deaths in American men. Androgen deprivation therapies (ADTs) that interfere with interactions between AR and its activating androgen ligands have been the mainstay for treatment of metastatic CaP. Although ADTs are effective and induce remissions, eventually they fail, while the growth of the majority of ADT-resistant CaPs remains under AR’s control. Alternative approaches to inhibit AR activity and bypass resistance to ADT are being sought, such as preventing the interaction between AR and its cofactors and coregulators that is needed to execute AR-dependent transcription. For such strategies to be efficient, the 3D conformation of AR complexes needs to be well-understood and AR-regulator interaction sites resolved. Here, we review current insights into these 3D structures and the protein interaction sites in AR transcriptional complexes. We focus on methods and technological approaches used to identify AR interactors and discuss challenges and limitations that need to be overcome for efficient therapeutic AR complex disruption.
Keywords	androgen deprivation therapy ; hormonal therapy ; transcription ; coactivators ; corepressors ; proteomics ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genomic alterations impact cell cycle-related genes during prostate cancer progression.

Ben-Salem, Salma / Venkadakrishnan, Varadha Balaji / Heemers, Hannelore V

Endocrine-related cancer

2021 Volume 28, Issue 6, Page(s) L5–L10

Abstract: The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such ... ...

Abstract	The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such alterations impact hallmarks of cancer is still unclear. Here, we interrogate genomic data from thousands of clinical CaP specimens that reflect progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP for alterations in cell cycle-associated and -regulated genes, which are central to cancer initiation and progression. We evaluate gene signatures previously curated to evaluate G1-S and G2-M phase transitions or to represent the cell cycle-dependent proteome. The resulting CaP (stage)-specific overview confirmed the presence of well-known driver alterations impacting, for instance, the genes encoding p53 and MYC, and uncovered novel previously unrecognized mutations that affect others such as the PKMYT1 and MTBP genes. The cancer dependency and drugability of representative genomically altered cell cycle determinants were verified also. Taken together, these analyses on hundreds of often less-characterized cell cycle regulators expand considerably the scope of genomic alterations associated with CaP cell proliferation and cell cycle and isolate such regulatory proteins as putative drivers of CaP treatment resistance and entirely novel therapeutic targets for CaP therapy.
MeSH term(s)	Cell Cycle/genetics ; Humans ; Male ; Membrane Proteins ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/therapy ; Protein Serine-Threonine Kinases ; Protein-Tyrosine Kinases
Chemical Substances	Membrane Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; PKMYT1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-05-11
Publishing country	England
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-21-0091
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4192: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Novel insights in cell cycle dysregulation during prostate cancer progression.

Ben-Salem, Salma / Venkadakrishnan, Varadha Balaji / Heemers, Hannelore V

Endocrine-related cancer

2021 Volume 28, Issue 6, Page(s) R141–R155

Abstract: Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced ... ...

Abstract	Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.
MeSH term(s)	Cell Cycle ; Cell Division ; Disease Progression ; Humans ; Male ; Prostate/metabolism ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Receptors, Androgen/metabolism
Chemical Substances	Receptors, Androgen
Language	English
Publishing date	2021-05-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-20-0517
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4192: Show issues

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Article ; Online: Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.

Maw, Joshua J / Coker, Jesse A / Arya, Tarun / Goins, Christopher M / Sonawane, Dhiraj / Han, Sang Hoon / Rees, Matthew G / Ronan, Melissa M / Roth, Jennifer A / Wang, Nancy S / Heemers, Hannelore V / Macdonald, Jonathan D / Stauffer, Shaun R

Journal of medicinal chemistry

2024 Volume 67, Issue 4, Page(s) 2631–2666

Abstract: Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor ... ...

Abstract	Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe,
MeSH term(s)	Humans ; Protein Serine-Threonine Kinases/metabolism ; Cell Division ; Cytokinesis/physiology ; Phosphorylation ; Cell Proliferation
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01807
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MB 1: Show issues

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