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Article ; Online: AKR1C3 mediates pan-AR antagonist resistance in castration-resistant prostate cancer.

Hertzog, Jennifer R / Zhang, Zhuming / Bignan, Gilles / Connolly, Peter J / Heindl, Jason E / Janetopoulos, Christopher J / Rupnow, Brent A / McDevitt, Theresa M

The Prostate

2020 Volume 80, Issue 14, Page(s) 1223–1232

Abstract: Background: Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration-resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to ... ...

Abstract	Background: Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration-resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to these therapies within 2 years. JNJ-pan-AR is a broad-spectrum AR antagonist that inhibits wild-type AR as well as several mutated versions of AR that have emerged in patients on chronic antiandrogen treatment. In this work, we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ-pan-AR treatment. Methods: The LNCaP JNJR prostate cancer subline was developed by chronically exposing LNCaP parental cells to JNJ-pan-AR. Transcriptomic and proteomic profiling was performed to identify potential drivers and/or biomarkers of the resistant phenotype. Results: Several enzymes critical to intratumoral androgen biosynthesis, Aldo-keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17 were identified as potential upstream regulators of the JNJ-pan-AR resistant cells. While we confirmed the overexpression of all three enzymes in the resistant cells only AKR1C3 expression played a functional role in driving JNJ-pan-AR resistance. We also discovered that AKR1C3 regulates UGT2B15 and UGT2B17 expression in JNJ-pan-AR resistant cells. Conclusions: This study supports the rationale to further investigate the benefits of AKR1C3 inhibition in combination with antiandrogens to prevent CRPC disease progression.
MeSH term(s)	Aldo-Keto Reductase Family 1 Member C3/biosynthesis ; Aldo-Keto Reductase Family 1 Member C3/genetics ; Aldo-Keto Reductase Family 1 Member C3/metabolism ; Androgen Receptor Antagonists/pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Genomics ; Glucuronosyltransferase/biosynthesis ; Glucuronosyltransferase/genetics ; Glucuronosyltransferase/metabolism ; Humans ; Male ; Minor Histocompatibility Antigens/biosynthesis ; Minor Histocompatibility Antigens/genetics ; Minor Histocompatibility Antigens/metabolism ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Proteomics ; Receptors, Androgen/metabolism ; Transcription, Genetic
Chemical Substances	AR protein, human ; Androgen Receptor Antagonists ; Minor Histocompatibility Antigens ; Receptors, Androgen ; AKR1C3 protein, human (EC 1.1.1.357) ; Aldo-Keto Reductase Family 1 Member C3 (EC 1.1.1.357) ; Glucuronosyltransferase (EC 2.4.1.17) ; UDP-glucuronosyltransferase 2B15, human (EC 2.4.1.17) ; UGT2B17 protein, human (EC 2.4.1.17)
Language	English
Publishing date	2020-07-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	604707-5
ISSN	1097-0045 ; 0270-4137
ISSN (online)	1097-0045
ISSN	0270-4137
DOI	10.1002/pros.24049
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Zs.A 1608: Show issues

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Article ; Online: Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes.

Lercher, Lukas / Simon, Nina / Bergmann, Andreas / Tauchert, Marcel / Bochmann, David / Bashir, Tarig / Neuefeind, Torsten / Riley, Daniel / Danna, Ben / Krawczuk, Paul / Pande, Vineet / Patrick, Aaron / Steele, Ruth / Wang, Weixue / Rupnow, Brent / Tummino, Peter / Sharma, Sujata / Finley, Michael

SLAS discovery : advancing life sciences R & D

2022 Volume 27, Issue 5, Page(s) 306–313

Abstract: The dysregulation of the PRC1/2 complex plays a key role in lineage plasticity in prostate cancer and may be required to maintain neuroendocrine phenotype. [1] CBX2, a key component of the canonical PRC1 complex, is an epigenetic reader, recognizing ... ...

Abstract	The dysregulation of the PRC1/2 complex plays a key role in lineage plasticity in prostate cancer and may be required to maintain neuroendocrine phenotype. [1] CBX2, a key component of the canonical PRC1 complex, is an epigenetic reader, recognizing trimethylated lysine on histone 3 (H3K27me3) [2] and is overexpressed in metastatic neuroendocrine prostate cancer. [3,4] We implemented a screening strategy using nucleosome substrates to identify inhibitors of CBX2 binding to chromatin. Construct design and phosphorylation state of CBX2 were critical for successful implementation and execution of an HTS library screen. A rigorous screening funnel including counter and selectivity assays allowed us to quickly focus on true positive hit matter. Two distinct non-peptide-like chemotypes were identified and confirmed in orthogonal biochemical and biophysical assays demonstrating disruption of CBX2 binding to nucleosomes and direct binding to purified CBX2, respectively.
MeSH term(s)	Cell Nucleus/metabolism ; Chromatin ; Histones/metabolism ; Humans ; Male ; Polycomb Repressive Complex 1/genetics ; Prostatic Neoplasms/metabolism
Chemical Substances	CBX2 protein, human ; Chromatin ; Histones ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2885123-7
ISSN	2472-5560 ; 2472-5552
ISSN (online)	2472-5560
ISSN	2472-5552
DOI	10.1016/j.slasd.2022.04.003
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Zs.A 4911: Show issues

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Article ; Online: The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

Van Emmenis, Lucie / Ku, Sheng-Yu / Gayvert, Kaitlyn / Branch, Jonathan R / Brady, Nicholas J / Basu, Subhasree / Russell, Michael / Cyrta, Joanna / Vosoughi, Aram / Sailer, Verena / Alnajar, Hussein / Dardenne, Etienne / Koumis, Elena / Puca, Loredana / Robinson, Brian D / Feldkamp, Michael D / Winkis, Annmarie / Majewski, Nathan / Rupnow, Brent /

Gottardis, Marco M / Elemento, Olivier / Rubin, Mark A / Beltran, Himisha / Rickman, David S

Cancer research communications

2023 Volume 3, Issue 8, Page(s) 1447–1459

Abstract: Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative ... ...

Abstract	Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration Significance: The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.
MeSH term(s)	Humans ; Male ; Prostatic Neoplasms/genetics ; Neuroendocrine Tumors/genetics ; Prostate/metabolism ; Cell Membrane/metabolism ; Cadherins/genetics
Chemical Substances	Cadherins
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0491
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Article ; Online: Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.

Richters, André / Doyle, Shelby K / Freeman, David B / Lee, Christina / Leifer, Becky S / Jagannathan, Sajjeev / Kabinger, Florian / Koren, Jošt Vrabič / Struntz, Nicholas B / Urgiles, Julie / Stagg, Ryan A / Curtin, Brice H / Chatterjee, Deep / Mathea, Sebastian / Mikochik, Peter J / Hopkins, Tamara D / Gao, Hua / Branch, Jonathan R / Xin, Hong /

Cell chemical biology

2020 Volume 28, Issue 2, Page(s) 134–147.e14

Abstract: Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant ...

Abstract	Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
MeSH term(s)	Androgen Receptor Antagonists/pharmacology ; Androgen Receptor Antagonists/therapeutic use ; Animals ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Cyclin-Dependent Kinase 9/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Receptors, Androgen/genetics ; Transcription, Genetic/drug effects
Chemical Substances	Androgen Receptor Antagonists ; Protein Kinase Inhibitors ; Receptors, Androgen ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
Language	English
Publishing date	2020-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2020.10.001
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Article ; Online: Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy.

Roongta, Urvashi V / Pabalan, Jonathan G / Wang, Xinyu / Ryseck, Rolf-Peter / Fargnoli, Joseph / Henley, Benjamin J / Yang, Wen-Pin / Zhu, Jun / Madireddi, Malavi T / Lawrence, R Michael / Wong, Tai W / Rupnow, Brent A

Molecular cancer research : MCR

2011 Volume 9, Issue 11, Page(s) 1551–1561

Abstract: Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. ... ...

Abstract	Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that desaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Growth Processes/physiology ; Cell Line, Tumor ; Cell Survival/physiology ; Fatty Acids, Unsaturated/metabolism ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Sequence Data ; Molecular Targeted Therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; Stearoyl-CoA Desaturase/antagonists & inhibitors ; Stearoyl-CoA Desaturase/biosynthesis ; Stearoyl-CoA Desaturase/deficiency ; Stearoyl-CoA Desaturase/genetics ; Stearoyl-CoA Desaturase/metabolism ; Transfection
Chemical Substances	Fatty Acids, Unsaturated ; RNA, Small Interfering ; SCD1 protein, human (EC 1.14.19.1) ; SCD5 protein, human (EC 1.14.19.1) ; Stearoyl-CoA Desaturase (EC 1.14.19.1)
Language	English
Publishing date	2011-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-11-0126
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Zs.A 5744: Show issues

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Article: Synthetic lethality of retinoblastoma mutant cells in the Drosophila eye by mutation of a novel peptidyl prolyl isomerase gene.

Genetics

2005 Volume 170, Issue 1, Page(s) 161–171

Abstract: Mutations that inactivate the retinoblastoma (Rb) pathway are common in human tumors. Such mutations promote tumor growth by deregulating the G1 cell cycle checkpoint. However, uncontrolled cell cycle progression can also produce new liabilities for cell ...

Abstract	Mutations that inactivate the retinoblastoma (Rb) pathway are common in human tumors. Such mutations promote tumor growth by deregulating the G1 cell cycle checkpoint. However, uncontrolled cell cycle progression can also produce new liabilities for cell survival. To uncover such liabilities in Rb mutant cells, we performed a clonal screen in the Drosophila eye to identify second-site mutations that eliminate Rbf(-) cells, but allow Rbf(+) cells to survive. Here we report the identification of a mutation in a novel highly conserved peptidyl prolyl isomerase (PPIase) that selectively eliminates Rbf(-) cells from the Drosophila eye.
MeSH term(s)	Amino Acid Sequence ; Animals ; Drosophila melanogaster/embryology ; Drosophila melanogaster/enzymology ; Drosophila melanogaster/genetics ; Eye/embryology ; Eye/enzymology ; Molecular Sequence Data ; Mutation ; Peptidylprolyl Isomerase/genetics ; Retinoblastoma Protein/genetics
Chemical Substances	Retinoblastoma Protein ; Peptidylprolyl Isomerase (EC 5.2.1.8)
Language	English
Publishing date	2005-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.104.036343
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Zs.B 767: Show issues

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Article: Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.

Cancer research

2005 Volume 65, Issue 9, Page(s) 3781–3787

Abstract: The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing ... ...

Abstract	The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Animals ; CD8 Antigens/biosynthesis ; CD8 Antigens/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Female ; Humans ; Mammary Neoplasms, Experimental/enzymology ; Mammary Neoplasms, Experimental/genetics ; Mammary Neoplasms, Experimental/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred ICR ; Mice, Nude ; Mice, Transgenic ; Neoplasm Transplantation ; Pregnancy ; Receptor, IGF Type 1/antagonists & inhibitors ; Receptor, IGF Type 1/biosynthesis ; Receptor, IGF Type 1/genetics ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/genetics ; Salivary Gland Neoplasms/enzymology ; Salivary Gland Neoplasms/genetics ; Salivary Gland Neoplasms/pathology ; Transfection ; Transgenes/genetics ; Transplantation, Heterologous
Chemical Substances	CD8 Antigens ; Recombinant Fusion Proteins ; Receptor, IGF Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2005-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-04-4602
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Article ; Online: AKR1C3 mediates pan-AR antagonist resistance in castration-resistant prostate cancer.

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Article ; Online: Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes.

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Article ; Online: The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

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Article ; Online: Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.

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Article ; Online: Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy.

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Article: Synthetic lethality of retinoblastoma mutant cells in the Drosophila eye by mutation of a novel peptidyl prolyl isomerase gene.

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Article: Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.

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