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Wang R, Wang S, Mi Y, Huang T, Wang J, Ni J, Wang J, Yin J, Li M, Ran X, Fan S, Sun Q, Tan SY, Phillip Koeffler H, Ding L, Chen YQ, Feng N. Elevated serum levels of GPX4, NDUFS4, PRDX5, and TXNRD2 as predictive biomarkers for castration resistance in prostate cancer patients: an exploratory study. Br J Cancer 2025; 132:543-557. [PMID: 39900986 PMCID: PMC11920399 DOI: 10.1038/s41416-025-02947-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 12/24/2024] [Accepted: 01/21/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a heterogeneous disease affecting over 14% of the male population worldwide. Although patients often respond positively to initial treatments within the first 2-3 years, many eventually develop a more lethal form of the disease known as castration-resistant PCa (CRPC). At present, no biomarkers that predict the onset of CRPC are available. This study aims to provide insights into the diagnosis and prediction of CRPC emergence. METHODS Protein expression dynamics were analysed in drug (androgen receptor inhibitor)-tolerant persister (DTP) and drug withdrawal cells using proteomics to identify potential biomarkers. These biomarkers were subsequently validated using a mouse model, 180-paired carcinoma/benign tissues, and 482 serum samples. Five machine learning algorithms were employed to build clinical prediction models, wherein the SHapley Additive exPlanation (SHAP) framework was used to interpret the best-performing model. Moreover, three regression models were developed to determine the Time from initial PCa diagnosis to CRPC development (TPC) in patients. RESULTS We identified that the protein expression levels of GPX4, NDUFS4, PRDX5, and TXNRD2 were significantly upregulated in PCa patients, particularly in those with CRPC. Among the tested machine learning models, the random forest and extreme gradient boosting models performed best on tissue and serum cohorts, achieving AUCs of 0.958 and 0.988, respectively. In addition, a significant inverse correlation was observed between TPC and serum levels of these four biomarkers. This correlation was formulated in three regression models, which achieved the smallest mean absolute error of 1.903 on independent datasets for predicting CRPC emergence. CONCLUSION Our study provides new insights into the role of DTP cells in CRPC development. The quad protein panel identified in our study, along with the post hoc and intrinsically explainable prediction models, may serve as a convenient and real-time prognostic tool, addressing the current lack of clinical biomarkers for CRPC.
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Affiliation(s)
- Rong Wang
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Shaopeng Wang
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China
| | - Yuanyuan Mi
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Tianyi Huang
- School of Computing, National University of Singapore, Singapore, Singapore
| | - Jun Wang
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jiang Ni
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jian Wang
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Menglu Li
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China
- Department of Urology, Wuxi No.2 People's Hospital, Nanjing Medical University, Wuxi, China
| | - Xuebin Ran
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Shuangyi Fan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Qiaoyang Sun
- Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
| | - Soo Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - H Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, California, Los Angeles, CA, USA
| | - Lingwen Ding
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Yong Q Chen
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China.
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
| | - Ninghan Feng
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China.
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
- Department of Urology, Wuxi No.2 People's Hospital, Nanjing Medical University, Wuxi, China.
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Wu F, Zhang H, Hao M. Interactions between key genes and pathways in prostate cancer progression and therapy resistance. Front Oncol 2025; 15:1467540. [PMID: 39917165 PMCID: PMC11799259 DOI: 10.3389/fonc.2025.1467540] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Prostate cancer is one of the most prevalent malignant tumors in men, particularly in regions with a high Human Development Index. While the long-term survival rate for localized prostate cancer is relatively high, the mortality rate remains significantly elevated once the disease progresses to advanced stages, even with various intensive treatment modalities. The primary obstacle to curing advanced prostate cancer is the absence of comprehensive treatment strategies that effectively target the highly heterogeneous tumors at both genetic and molecular levels. Prostate cancer development is a complex, multigenic, and multistep process that involves numerous gene mutations, alteration in gene expression, and changes in signaling pathways. Key genetic and pathway alterations include the amplification and/or mutation of the androgen receptor, the loss of Rb, PTEN, and p53, the activation of the WNT signaling pathway, and the amplification of the MYC oncogene. This review summarizes the mechanisms by which these genes influence the progression of prostate cancer and highlights the interactions between multiple genes and their relationship with prostate cancer. Additionally, we reviewed the current state of treatments targeting these genes and signaling pathways, providing a comprehensive overview of therapeutic approaches in the context of prostate cancer.
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Affiliation(s)
- Fan Wu
- Department of Pathology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hengsen Zhang
- Department of Neurosurgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Miaomiao Hao
- Department of Pathology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Zhang L, Troccoli CI, Mateo-Victoriano B, Lincheta LM, Jackson E, Shu P, Plastini T, Tao W, Kwon D, Chen XS, Sharma J, Jorda M, Kumar S, Lombard DB, Gulley JL, Bilusic M, Lockhart AC, Beuve A, Rai P. Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer. Cancer Res 2025; 85:134-153. [PMID: 39388307 PMCID: PMC11695179 DOI: 10.1158/0008-5472.can-24-0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 06/27/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024]
Abstract
Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. In this study, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and cotreatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized the tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy. Significance: Soluble guanylyl cyclase signaling inhibits castration-resistant prostate cancer emergence and can be stimulated with FDA-approved riociguat to resensitize resistant tumors to androgen deprivation, providing a strategy to prevent and treat castration resistance.
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Affiliation(s)
- Ling Zhang
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Clara I. Troccoli
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Beatriz Mateo-Victoriano
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136
| | | | - Erin Jackson
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Ping Shu
- Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School- Rutgers, Newark, NJ, 07103, USA
| | - Trisha Plastini
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Wensi Tao
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - Deukwoo Kwon
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Present address: Department of Internal Medicine, UT Health Science Center at Houston, Houston, TX 77019
| | - X. Steven Chen
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - Janaki Sharma
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - Merce Jorda
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - Surinder Kumar
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - David B. Lombard
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
- Miami VA Healthcare System, Miami FL 33125
| | - James L. Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892
| | - Marijo Bilusic
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
| | - Albert C. Lockhart
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
- Present address: Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29706
| | - Annie Beuve
- Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School- Rutgers, Newark, NJ, 07103, USA
| | - Priyamvada Rai
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miami, FL 33135
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Lu T, Liao B, Lin R, Meng C, Huang P, Wang C, Liu F, Xia C. 18β-Glycyrrhetinic acid synergizes with enzalutamide to counteract castration-resistant prostate cancer by inhibiting OATP2B1 uptake of dehydroepiandrosterone sulfate. Eur J Pharmacol 2024; 983:176995. [PMID: 39277096 DOI: 10.1016/j.ejphar.2024.176995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/07/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
Androgen dependence is a key feature of prostate cancer, and androgen deprivation is effective in treating prostate cancer. However, the disease often worsens and develops into castration-resistant prostate cancer after short-term control. The current study aimed to explore the mechanism of the synergistic action of 18β-glycyrrhetinic acid (18β-GA) and enzalutamide (ENZ) against prostate cancer. Our findings showed that 18β-GA significantly inhibited the expression of OATP2B1 and the transport of dehydroepiandrosterone sulfate (DHEAS) in LNCap and 22RV1 cells. It also downregulated the expression of androgen receptor (AR) to some extent. ENZ strongly inhibited AR expression, but it did not affect OATP2B1-mediated uptake of DHEAS. Compared to the effects of 18β-GA and ENZ alone, the combination of 18β-GA and ENZ significantly enhanced the inhibitory effects on AR, prostate-specific antigen (PSA) expression, tumor cell proliferation, and migration. The results obtained in castrated model mice matched the findings of in vitro experiments. 18β-GA significantly reduced the uptake of DHEAS mediated by OATP2B1 in mouse tumor tissues and cooperated with ENZ to further inhibit the expression of AR and PSA, combat the growth of tumor cells, and promote the apoptosis of tumor cells. In conclusion, 18β-GA considerably decreased the uptake of DHEAS and androgen production in cells by inhibiting the transport function of OATP2B1, while ENZ inhibited the nuclear translocation of AR and reduced the expression of AR. The combination of 18β-GA and ENZ can simultaneously inhibit androgen production and AR expression and exhibit a synergistic effect against castration and prostate cancer progression.
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Affiliation(s)
- Ting Lu
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China
| | - Bin Liao
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China
| | - Ronghe Lin
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China
| | - Chao Meng
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China
| | - Ping Huang
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China
| | - Cheng Wang
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, 330031, PR China
| | - Fanglan Liu
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, 330031, PR China.
| | - Chunhua Xia
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, PR China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, 330031, PR China.
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Pirsl F, Calkins K, Rudolph JE, Wentz E, Xu X, Lau B, Joshu CE. Incidence of prostate cancer in Medicaid beneficiaries with and without HIV in 2001-2015 in 14 states. AIDS Care 2024; 36:1657-1667. [PMID: 39079500 PMCID: PMC11511642 DOI: 10.1080/09540121.2024.2383875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 07/18/2024] [Indexed: 08/07/2024]
Abstract
Prostate cancer (PCa) incidence is reportedly lower in men with HIV compared to men without HIV for unknown reasons. We describe PCa incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare. Men (N = 15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and PCa were identified using non-drug claims. We estimated cause-specific (csHR) comparing incidence of PCa by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions, and stratified by age and race-ethnicity. Hazard of PCa was lower in men with HIV than men without HIV (csHR = 0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR = 0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR = 0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR = 1.17; 95% CI: 0.91, 1.50). Findings were similar in models restricted to men aged 50-64 and 40-49, but not in men aged 18-39. Reported deficits in PCa incidence by HIV status may be restricted to specific groups defined by age and race ethnicity.
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Affiliation(s)
- Filip Pirsl
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Keri Calkins
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Mathematica, Ann Arbor, Michigan, United States
| | - Jacqueline E. Rudolph
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Eryka Wentz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Xiaoqiang Xu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Bryan Lau
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States
- Department of Medicine, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Corinne E. Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States
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Wilson TK, Zishiri OT. Prostate Cancer: A Review of Genetics, Current Biomarkers and Personalised Treatments. Cancer Rep (Hoboken) 2024; 7:e70016. [PMID: 39410867 PMCID: PMC11480670 DOI: 10.1002/cnr2.70016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/22/2024] [Accepted: 09/09/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Prostate cancer is the second leading cause of cancer deaths in men, second only to lung cancer. Despite this, diagnosis and prognosis methods remain limited, with effective treatments being few and far between. Traditionally, prostate cancer is initially tested for through a prostate serum antigen (PSA) test and a digital rectum examination (DRE), followed by confirmation through an invasive prostate biopsy. The DRE and biopsy are uncomfortable for the patient, so less invasive, accurate diagnostic tools are needed. Current diagnostic tools, along with genes that hold possible biomarker uses in diagnosis, prognosis and indications for personalised treatment plans, were reviewed in this article. RECENT FINDINGS Several genes from multiple families have been identified as possible biomarkers for disease, including those from the MYC and ETS families, as well as several tumour suppressor genes, Androgen Receptor signalling genes and DNA repair genes. There have also been advances in diagnostic tools, including MRI-targeted and liquid biopsies. Several personalised treatments have been developed over the years, including those that target metabolism-driven prostate cancer or those that target inflammation-driven cancer. CONCLUSION Several advances have been made in prostate cancer diagnosis and treatment, but the disease still grows year by year, leading to more and more deaths annually. This calls for even more research into this disease, allowing for better diagnosis and treatment methods and a better chance of patient survival.
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Affiliation(s)
- Trevor K. Wilson
- Discipline of Genetics, School of Life Sciences, College of Agriculture, Engineering, and ScienceUniversity of KwaZulu‐NatalDurbanSouth Africa
| | - Oliver T. Zishiri
- Discipline of Genetics, School of Life Sciences, College of Agriculture, Engineering, and ScienceUniversity of KwaZulu‐NatalDurbanSouth Africa
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7
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Wang R, Pan Y, Zhang L, Wang J, Ni J, Ding Y, Wang S, Yin J, Ding L, Ran X, Fan S, Sun Q, Tan SY, Koeffler HP, Li J, Mi Y, Chen YQ. Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development. Int J Biol Macromol 2024; 278:134844. [PMID: 39168191 DOI: 10.1016/j.ijbiomac.2024.134844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/08/2024] [Accepted: 08/16/2024] [Indexed: 08/23/2024]
Abstract
Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 μg/mL, 0.14 μg/mL, and 0.2-0.3 μg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 μg/mg) is 10-fold higher than that in normal prostate tissues (0.14 μg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.
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Affiliation(s)
- Rong Wang
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China; School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Yu Pan
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lan Zhang
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jun Wang
- First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China; Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jiang Ni
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Yang Ding
- College of Pharmacy, Pharmaceutical Series, China Pharmaceutical University, Nanjing, China
| | - Shaopeng Wang
- Jiangnan University Medical Center, Jiangnan University, Wuxi, China
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Lingwen Ding
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xuebin Ran
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Shuangyi Fan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Qiaoyang Sun
- Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
| | - Soo Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - H Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, CA, Los Angeles, USA
| | - Jie Li
- First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
| | - Yuanyuan Mi
- Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
| | - Yong Q Chen
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China; School of Food Science and Technology, Jiangnan University, Wuxi, China.
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Adida S, Taori S, Donohue JK, Rajan A, Sefcik RK, Burton SA, Flickinger JC, Gerszten PC. Stereotactic radiosurgery for patients with spinal metastases from prostate cancer. J Neurooncol 2024:10.1007/s11060-024-04821-0. [PMID: 39316317 DOI: 10.1007/s11060-024-04821-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
PURPOSE Spinal metastases may result in intractable pain, neurological deficit, and vertebral body collapse. There are only a few studies describing outcomes following spine stereotactic radiosurgery (SRS) specifically for prostate cancer metastases. METHODS A prospectively collected database of patients with prostate cancer spinal metastases treated at the University of Pittsburgh Medical Center from 2003 to 2023 was analyzed. The primary outcome was local control (LC). Secondary outcomes were overall survival (OS), pain resolution, and adverse radiation effects (AREs). RESULTS Thirty-seven patients and 51 lesions were identified. Fifteen lesions (29%) were previously resected and 34 lesions (67%) were previously irradiated. The median tumor volume was 37.0 cc (range: 2.9-263.3). A majority of lesions (71%) were treated in a single fraction (median 20 Gy, range: 14-22.5); multi-fractionated treatment consisted of 21-30 Gy in 2-5 fractions. Median follow-up was 12 months (range: 1-146). The 6-month, 1-year, and 2-year LC rates were 97%, 91%, and 91%, respectively. No tested prognostic factors were associated with LC, including hormone sensitivity. The 6-month, 1-year, and 2-year OS rates were 71%, 56%, and 32%; age > 70 years (p = 0.048) and tumor volume > 30 cc (p = 0.03) were associated with inferior rates of OS. Complete or partial pain response was observed in 58% of patients. There were 8 instances (16%) of AREs, 2 of which were vertebral compression fractures (4%). CONCLUSION Radiosurgery as a primary or adjuvant treatment modality for prostate cancer spinal metastases confers durable LC and moderate pain relief with minimal toxicity. Further studies are warranted to optimize management in this patient population.
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Affiliation(s)
- Samuel Adida
- School of Medicine, University of Pittsburgh Medical Center, 3550 Terrace St, Pittsburgh, PA, 15213, USA.
- Department of Neurological Surgery, University of Pittsburgh Medical Center, 200 Lothrop St Suite B-400, Pittsburgh, PA, 15213, USA.
| | - Suchet Taori
- School of Medicine, University of Pittsburgh Medical Center, 3550 Terrace St, Pittsburgh, PA, 15213, USA
- Department of Neurological Surgery, University of Pittsburgh Medical Center, 200 Lothrop St Suite B-400, Pittsburgh, PA, 15213, USA
| | - Jack K Donohue
- School of Medicine, University of Pittsburgh Medical Center, 3550 Terrace St, Pittsburgh, PA, 15213, USA
| | - Akshath Rajan
- School of Medicine, University of Pittsburgh Medical Center, 3550 Terrace St, Pittsburgh, PA, 15213, USA
| | - Roberta K Sefcik
- Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
| | - Steven A Burton
- Department of Radiation Oncology, University of Pittsburgh Medical Center, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
| | - John C Flickinger
- Department of Radiation Oncology, University of Pittsburgh Medical Center, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
| | - Peter C Gerszten
- Department of Neurological Surgery, University of Pittsburgh Medical Center, 200 Lothrop St Suite B-400, Pittsburgh, PA, 15213, USA
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9
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Hinojosa-Gonzalez DE, Zafar A, Saffati G, Kronstedt S, Zlatev DV, Khera M. Androgen deprivation therapy for prostate cancer and neurocognitive disorders: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2024; 27:507-519. [PMID: 38167924 DOI: 10.1038/s41391-023-00785-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/29/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Prostate cancer is a prevalent disease that urgently needs to address its treatment-related complications. By examining existing evidence on the association between Androgen Deprivation Therapy (ADT) and dementia, this study contributes to the understanding of potential risks. We sought to analyze the currently available evidence regarding the risk of dementia, Alzheimer's disease (AD), vascular dementia, and Parkinson's disease (PD) in patients undergoing ADT. METHODS A systematic search of PubMed, EMBASE, Scopus, and Google Scholar was performed to identify studies published from the databases' inception to April 2023. Studies were identified through systematic review to facilitate comparisons between studies with and without some degree of controls for biases affecting distinctions between ADT receivers and non-ADT receivers. This review identified 305 studies, with 28 meeting the inclusion criteria. Heterogeneity was assessed using Higgins I2%. Variables with an I2 over 50% were considered heterogeneous and analyzed using a Random-Effects model. Otherwise, a Fixed-Effects model was employed. RESULTS A total of 28 studies were included for analysis. Out of these, only 1 study did not report the number of patients. From the remaining 27 studies, there were a total of 2,543,483 patients, including 900,994 with prostate cancer who received ADT, 1,262,905 with prostate cancer who did not receive ADT, and 334,682 patients without prostate cancer who did not receive ADT. This analysis revealed significantly increased Hazard Ratios (HR) of 1.20 [1.11, 1.29], p < 0.00001 for dementia, HR 1.26 [1.10, 1.43], p = 0.0007 for Alzheimer's Disease, HR 1.66 [1.40, 1.97], p < 0.00001 for depression, and HR 1.57 [1.31, 1.88], p < 0.00001 for Parkinson's Disease. The risk of vascular dementia was HR 1.30 [0.97, 1.73], p < 0.00001. CONCLUSION Based on the analysis of the currently available evidence, it suggests that ADT significantly increases the risk of dementia, AD, PD, and depression.
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Affiliation(s)
- David E Hinojosa-Gonzalez
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB 1102, Boston, MA, 02114, USA.
| | - Affan Zafar
- Scott Department of Urology, Baylor College of Medicine, 7200 Cambridge Street, Houston, TX, 77030, USA
| | - Gal Saffati
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB 1102, Boston, MA, 02114, USA
| | - Shane Kronstedt
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB 1102, Boston, MA, 02114, USA
| | - Dimitar V Zlatev
- Scott Department of Urology, Baylor College of Medicine, 7200 Cambridge Street, Houston, TX, 77030, USA
| | - Mohit Khera
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB 1102, Boston, MA, 02114, USA
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10
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Pirsl F, Calkins K, Rudolph JE, Wentz E, Xu X, Lau B, Joshu CE. Incidence of prostate cancer in Medicaid beneficiaries with and without HIV in 2001-2015 in 14 states. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.24.24307676. [PMID: 38826404 PMCID: PMC11142281 DOI: 10.1101/2024.05.24.24307676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Background Prostate cancer is projected to be the most common cancer among people living with HIV; however, incidence of prostate cancer has been reported to be lower in men with HIV compared to men without HIV with little evidence to explain this difference. We describe prostate cancer incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare. Methods Medicaid beneficiaries (N=15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and prostate cancer were identified using inpatient and other non-drug claims. We estimated cause-specific (csHR) and sub-distribution hazard ratios comparing incidence of prostate cancer by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions. Models were additionally stratified by age and race-ethnicity. Results There were 366 cases of prostate cancer observed over 299,976 person-years among beneficiaries with HIV and 17,224 cases over 22,298,914 person-years in beneficiaries without HIV. The hazard of prostate cancer was lower in men with HIV than men without HIV (csHR=0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR=0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR=0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR=1.17; 95% CI: 0.91, 1.50). Results were similar in models restricted to ages 50-64 and 40-49, except for a higher hazard of prostate cancer in Hispanic men with HIV in their 40s, while the hazard of prostate cancer was higher in men with HIV across all models for men aged 18-39. Conclusion Reported deficits in prostate cancer incidence by HIV status may be restricted to specific groups defined by age and race-ethnicity.
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Affiliation(s)
- Filip Pirsl
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Keri Calkins
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Mathematica, Ann Arbor, Michigan, United States
| | - Jacqueline E. Rudolph
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Eryka Wentz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Xiaoqiang Xu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Bryan Lau
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States
- Department of Medicine, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Corinne E. Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States
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11
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van Genderen MNG, Kneppers J, Zaalberg A, Bekers EM, Bergman AM, Zwart W, Eduati F. Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties. NPJ Syst Biol Appl 2024; 10:20. [PMID: 38383542 PMCID: PMC10881528 DOI: 10.1038/s41540-024-00344-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/25/2024] [Indexed: 02/23/2024] Open
Abstract
Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, "pro-inflammatory" M1-like and "pro-tumor" M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development.
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Affiliation(s)
- Maisa N G van Genderen
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Jeroen Kneppers
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Anniek Zaalberg
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Elise M Bekers
- Division of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Andries M Bergman
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Division of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - Wilbert Zwart
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands.
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands.
| | - Federica Eduati
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands.
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12
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Guerrero-Ochoa P, Rodríguez-Zapater S, Anel A, Esteban LM, Camón-Fernández A, Espilez-Ortiz R, Gil-Sanz MJ, Borque-Fernando Á. Prostate Cancer and the Mevalonate Pathway. Int J Mol Sci 2024; 25:2152. [PMID: 38396837 PMCID: PMC10888820 DOI: 10.3390/ijms25042152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/04/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.
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Affiliation(s)
- Patricia Guerrero-Ochoa
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
| | - Sergio Rodríguez-Zapater
- Minimally Invasive Research Group (GITMI), Faculty of Veterinary Medicine, University of Zaragoza, 50009 Zaragoza, Spain;
| | - Alberto Anel
- Department of Biochemistry and Molecular and Cellular Biology, Faculty of Sciences, University of Zaragoza, 50009 Zaragoza, Spain;
| | - Luis Mariano Esteban
- Department of Applied Mathematics, Escuela Universitaria Politécnica de La Almunia, Institute for Biocomputation and Physic of Complex Systems, Universidad de Zaragoza, 50100 La Almunia de Doña Godina, Spain
| | - Alejandro Camón-Fernández
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
| | - Raquel Espilez-Ortiz
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
- Area of Urology, Department of Surgery, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - María Jesús Gil-Sanz
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
| | - Ángel Borque-Fernando
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Applied Mathematics, Escuela Universitaria Politécnica de La Almunia, Institute for Biocomputation and Physic of Complex Systems, Universidad de Zaragoza, 50100 La Almunia de Doña Godina, Spain
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
- Area of Urology, Department of Surgery, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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13
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Alqualo NO, Campos-Fernandez E, Picolo BU, Ferreira EL, Henriques LM, Lorenti S, Moreira DC, Simião MPS, Oliveira LBT, Alonso-Goulart V. Molecular biomarkers in prostate cancer tumorigenesis and clinical relevance. Crit Rev Oncol Hematol 2024; 194:104232. [PMID: 38101717 DOI: 10.1016/j.critrevonc.2023.104232] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/17/2023] Open
Abstract
Prostate cancer (PCa) is the second most frequent type of cancer in men and assessing circulating tumor cells (CTCs) by liquid biopsy is a promising tool to help in cancer early detection, staging, risk of recurrence evaluation, treatment prediction and monitoring. Blood-based liquid biopsy approaches enable the enrichment, detection and characterization of CTCs by biomarker analysis. Hence, comprehending the molecular markers, their role on each stage of cancer development and progression is essential to provide information that can help in future implementation of these biomarkers in clinical assistance. In this review, we studied the molecular markers most associated with PCa CTCs to better understand their function on tumorigenesis and metastatic cascade, the methodologies utilized to analyze these biomarkers and their clinical significance, in order to summarize the available information to guide researchers in their investigations, new hypothesis formulation and target choice for the development of new diagnostic and treatment tools.
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Affiliation(s)
- Nathalia Oliveira Alqualo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Esther Campos-Fernandez
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Bianca Uliana Picolo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Emanuelle Lorrayne Ferreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Laila Machado Henriques
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Sabrina Lorenti
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Danilo Caixeta Moreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Maria Paula Silva Simião
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Luciana Beatriz Tiago Oliveira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Vivian Alonso-Goulart
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil.
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14
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Chien CH, Liu KL, Chuang CK, Wu CT, Chang YH, Yu KJ. Multimedia-based hormone therapy information program for patients with prostate cancer: the result of a randomized pilot study. Sci Rep 2023; 13:23022. [PMID: 38155164 PMCID: PMC10754917 DOI: 10.1038/s41598-023-50006-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/14/2023] [Indexed: 12/30/2023] Open
Abstract
Few studies have explored the feasibility and efficacy of a multimedia information intervention for patients with prostate cancer who are undergoing hormone therapy. Thus, the purpose of the study was to assess the feasibility, acceptability, and the preliminary results of a multimedia-based hormone therapy information program (HTIP) on positive thinking and quality of life (QOL; primary outcomes) as well as social support and self-efficacy (secondary outcomes) of patients with prostate cancer. Patients with prostate cancer who were receiving hormone therapy were recruited from hospitals. After completing the pre-test questionnaire, patients were randomly divided into the multimedia information group (MIG; n = 40) and the control group (CG; n = 40). Patients in the MIG received a multimedia-based HTIP once a week for 6 weeks. Data were collected at 8 and 12 weeks after the pre-test. Measurement variables included positive thinking, QOL, social support, self-efficacy, and satisfaction with the program. The recruitment rate and retention rate were calculated for assessment of feasibility. The study had a 96.3% retention rate, and patients in the MIG were satisfied with the program. Preliminary results showed that, compared with those in the CG, patients in the MIG tended to exhibit higher positive thinking, prostate cancer-specific QOL, and social support at 8 weeks and 12 weeks after pre-test; however, the effect did not reach a statistically significant level. A multimedia-based HTIP is considered feasible and acceptable in patients with prostate cancer who underwent hormone therapy. Further research with a larger sample size, patients with high homogeneity in early-stage disease and long-term follow-up is needed to assess the efficacy of the intervention program.Trial registration: ClinicalTrials.gov (NCT04693910); Registered 05/01/2021.
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Affiliation(s)
- Ching-Hui Chien
- School of Nursing, National Taipei University of Nursing and Health Sciences, No.365, Ming-te Road, Peitou District, Taipei City, 112, Taiwan.
| | - Kuan-Lin Liu
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan
| | - Cheng-Keng Chuang
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Tao-Yuan City, Taiwan
- College of Medicine, Chang Gung University, Tao-Yuan City, Taiwan
| | - Chun-Te Wu
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Tao-Yuan City, Taiwan
- College of Medicine, Chang Gung University, Tao-Yuan City, Taiwan
| | - Ying-Hsu Chang
- College of Medicine, Chang Gung University, Tao-Yuan City, Taiwan
- Division of Urology, Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, Taiwan
| | - Kai-Jie Yu
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Tao-Yuan City, Taiwan
- College of Medicine, Chang Gung University, Tao-Yuan City, Taiwan
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15
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Henry M, Riley CM, Hunter I, Elwood JML, Lopez-Fernandez JD, Minty L, Coe DM, McEwan IJ, Jamieson C. Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain. ACS Med Chem Lett 2023; 14:1800-1806. [PMID: 38116409 PMCID: PMC10726465 DOI: 10.1021/acsmedchemlett.3c00426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/10/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure-activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.
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Affiliation(s)
- Martyn
C. Henry
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
| | - Christopher M. Riley
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
| | - Irene Hunter
- Institute
of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
| | - Jessica M. L. Elwood
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
| | - J. Daniel Lopez-Fernandez
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
| | - Laura Minty
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
| | - Diane M. Coe
- Medicine
Design, GlaxoSmithKline R&D Ltd, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
| | - Iain J. McEwan
- Institute
of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
| | - Craig Jamieson
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
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16
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Riley CM, Elwood JML, Henry MC, Hunter I, Daniel Lopez-Fernandez J, McEwan IJ, Jamieson C. Current and emerging approaches to noncompetitive AR inhibition. Med Res Rev 2023; 43:1701-1747. [PMID: 37062876 DOI: 10.1002/med.21961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 04/18/2023]
Abstract
The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand-binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.
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Affiliation(s)
- Christopher M Riley
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
| | - Jessica M L Elwood
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
| | - Martyn C Henry
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
| | - Irene Hunter
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | | | - Iain J McEwan
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Craig Jamieson
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
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17
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Imamura J, Ganguly S, Muskara A, Liao RS, Nguyen JK, Weight C, Wee CE, Gupta S, Mian OY. Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution. Front Endocrinol (Lausanne) 2023; 14:1191311. [PMID: 37455903 PMCID: PMC10349394 DOI: 10.3389/fendo.2023.1191311] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN and AURKA amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3βHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.
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Affiliation(s)
- Jarrell Imamura
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Shinjini Ganguly
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Andrew Muskara
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Ross S. Liao
- Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Jane K. Nguyen
- Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Christopher Weight
- Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Christopher E. Wee
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Shilpa Gupta
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Omar Y. Mian
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
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18
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Striese F, Neuber C, Gräßel S, Arndt C, Ullrich M, Steinbach J, Pietzsch J, Bergmann R, Pietzsch HJ, Sihver W, Frenz M, Feldmann A, Bachmann MP. Preclinical Characterization of the 177Lu-Labeled Prostate Stem Cell Antigen (PSCA)-Specific Monoclonal Antibody 7F5. Int J Mol Sci 2023; 24:ijms24119420. [PMID: 37298374 DOI: 10.3390/ijms24119420] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/20/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Prostate specific membrane antigen (PSMA) is an excellent target for imaging and treatment of prostate carcinoma (PCa). Unfortunately, not all PCa cells express PSMA. Therefore, alternative theranostic targets are required. The membrane protein prostate stem cell antigen (PSCA) is highly overexpressed in most primary prostate carcinoma (PCa) cells and in metastatic and hormone refractory tumor cells. Moreover, PSCA expression positively correlates with tumor progression. Therefore, it represents a potential alternative theranostic target suitable for imaging and/or radioimmunotherapy. In order to support this working hypothesis, we conjugated our previously described anti-PSCA monoclonal antibody (mAb) 7F5 with the bifunctional chelator CHX-A″-DTPA and subsequently radiolabeled it with the theranostic radionuclide 177Lu. The resulting radiolabeled mAb ([177Lu]Lu-CHX-A″-DTPA-7F5) was characterized both in vitro and in vivo. It showed a high radiochemical purity (>95%) and stability. The labelling did not affect its binding capability. Biodistribution studies showed a high specific tumor uptake compared to most non-targeted tissues in mice bearing PSCA-positive tumors. Accordingly, SPECT/CT images revealed a high tumor-to-background ratios from 16 h to 7 days after administration of [177Lu]Lu-CHX-A″-DTPA-7F5. Consequently, [177Lu]Lu-CHX-A″-DTPA-7F5 represents a promising candidate for imaging and in the future also for radioimmunotherapy.
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Affiliation(s)
- Franziska Striese
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01062 Dresden, Germany
| | - Christin Neuber
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Sandy Gräßel
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01062 Dresden, Germany
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Martin Ullrich
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Jörg Steinbach
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01062 Dresden, Germany
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01062 Dresden, Germany
| | - Ralf Bergmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- Institute of Biophysics and Radiation Biology, Semmelweis University, 1094 Budapest, Hungary
| | - Hans-Jürgen Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Wiebke Sihver
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Marcus Frenz
- Faculty of Informatik and Wirtschaftsinformatik, Provadis School of International Management and Technology AG, 65926 Frankfurt, Germany
| | - Anja Feldmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
| | - Michael P Bachmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- National Center for Tumor Diseases (UCC/NCT), Partner Site Dresden, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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19
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Zhang L, Troccoli CI, Mateo-Victoriano B, Lincheta LM, Jackson E, Shu P, Plastini T, Tao W, Kwon D, Chen X, Sharma J, Jorda M, Gulley JL, Bilusic M, Lockhart AC, Beuve A, Rai P. The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.03.537252. [PMID: 37205442 PMCID: PMC10187243 DOI: 10.1101/2023.05.03.537252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC. Statement of significance Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.
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20
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Kumar R, Sena LA, Denmeade SR, Kachhap S. The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications. Nat Rev Urol 2023; 20:265-278. [PMID: 36543976 PMCID: PMC10164147 DOI: 10.1038/s41585-022-00686-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2022] [Indexed: 12/24/2022]
Abstract
The discovery of the benefits of castration for prostate cancer treatment in 1941 led to androgen deprivation therapy, which remains a mainstay of the treatment of men with advanced prostate cancer. However, as early as this original publication, the inevitable development of castration-resistant prostate cancer was recognized. Resistance first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of the androgen receptor axis. Evaluation of clinical specimens demonstrates that castration-resistant prostate cancer cells remain addicted to androgen signalling and adapt to chronic low-testosterone states. Paradoxically, results of several studies have suggested that treatment with supraphysiological levels of testosterone can retard prostate cancer growth. Insights from these studies have been used to investigate administration of supraphysiological testosterone to patients with prostate cancer for clinical benefits, a strategy that is termed bipolar androgen therapy (BAT). BAT involves rapid cycling from supraphysiological back to near-castration testosterone levels over a 4-week cycle. Understanding how BAT works at the molecular and cellular levels might help to rationalize combining BAT with other agents to achieve increased efficacy and tumour responses.
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Affiliation(s)
- Rajendra Kumar
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Laura A Sena
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Samuel R Denmeade
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Sushant Kachhap
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
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21
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Stangl A, Wilner C, Li P, Maahs L, Hwang C, Pilling A. Molecular features and race-associated outcomes of SPOP-mutant metastatic castration-resistant prostate cancer. Prostate 2023; 83:524-533. [PMID: 36604824 DOI: 10.1002/pros.24481] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/28/2022] [Accepted: 12/13/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)-mediated oncogenic signaling. The presence of SPOP mutation (SPOP-mutant [SPOP-mut]) may therefore impact therapeutic outcomes with AR-directed therapies and docetaxel in metastatic castration-resistant (mCRPC). METHODS This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP-mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second-generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate-specific antigen-progression-free survival [PSA-PFS]) compared by SPOP status using Kaplan-Meier curves and log-rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features. RESULTS SPOP-mut was associated with longer PSA-PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.17-0.84; p = 0.02). SPOP-mut demonstrated a higher median PSA decline compared to SPOP wild-type (median decline 100% vs. 92%, p = 0.02). SPOP-mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA-PFS on docetaxel (median PSA-PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race-associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA-PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co-occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017). CONCLUSIONS Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.
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Affiliation(s)
- Andrew Stangl
- Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Christopher Wilner
- Department of Internal Medicine, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan, USA
| | - Pin Li
- Depatment of Public Health Sciences, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan, USA
| | - Lucas Maahs
- Department of Internal Medicine, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan, USA
| | - Clara Hwang
- Department of Internal Medicine, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan, USA
| | - Amanda Pilling
- Department of Internal Medicine, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan, USA
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22
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Gogola S, Rejzer M, Bahmad HF, Abou-Kheir W, Omarzai Y, Poppiti R. Epithelial-to-Mesenchymal Transition-Related Markers in Prostate Cancer: From Bench to Bedside. Cancers (Basel) 2023; 15:cancers15082309. [PMID: 37190236 DOI: 10.3390/cancers15082309] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide, with 288,300 new cases and 34,700 deaths estimated in the United States in 2023. Treatment options for early-stage disease include external beam radiation therapy, brachytherapy, radical prostatectomy, active surveillance, or a combination of these. In advanced cases, androgen-deprivation therapy (ADT) is considered the first-line therapy; however, PCa in most patients eventually progresses to castration-resistant prostate cancer (CRPC) despite ADT. Nonetheless, the transition from androgen-dependent to androgen-independent tumors is not yet fully understood. The physiological processes of epithelial-to-non-epithelial ("mesenchymal") transition (EMT) and mesenchymal-to-epithelial transition (MET) are essential for normal embryonic development; however, they have also been linked to higher tumor grade, metastatic progression, and treatment resistance. Due to this association, EMT and MET have been identified as important targets for novel cancer therapies, including CRPC. Here, we discuss the transcriptional factors and signaling pathways involved in EMT, in addition to the diagnostic and prognostic biomarkers that have been identified in these processes. We also tackle the various studies that have been conducted from bench to bedside and the current landscape of EMT-targeted therapies.
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Affiliation(s)
- Samantha Gogola
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Michael Rejzer
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Hisham F Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Yumna Omarzai
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Robert Poppiti
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
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23
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Yang CK, Cha TL, Chang YH, Huang SP, Lin JT, Wang SS, Huang CY, Pang ST. Darolutamide for non-metastatic castration-resistant prostate cancer: Efficacy, safety, and clinical perspectives of use. J Formos Med Assoc 2023; 122:299-308. [PMID: 36797129 DOI: 10.1016/j.jfma.2022.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/23/2022] [Accepted: 12/12/2022] [Indexed: 02/16/2023] Open
Abstract
Darolutamide, a second-generation androgen receptor inhibitor (SGARI), has been shown to increase metastasis-free survival and overall survival among men with non-metastatic castration-resistant prostate cancer (nmCRPC). Its unique chemical structure potentially provides efficacy and safety advantages over the SGARIs apalutamide and enzalutamide, which are also indicated for nmCRPC. Despite a lack of direct comparisons, the SGARIs appear to have similar efficacy, safety, and quality of life (QoL) results. Indirect evidence suggests that darolutamide is preferred for its good adverse event profile, an attribute valued by physicians, patients, and their caregivers for maintaining QoL. Darolutamide and others in its class are costly; access may be a challenge for many patients and may lead to modifications to guideline-recommended regimens.
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Affiliation(s)
- Cheng-Kuang Yang
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taiwan
| | - Tai-Lung Cha
- Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taiwan
| | - Yen-Hwa Chang
- Division of General Urology, Department of Urology, Taipei Veterans General Hospital, Taiwan; Department of Urology, National Yang-Ming University School of Medicine, Taiwan
| | - Shu-Pin Huang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jen-Tai Lin
- Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Taiwan
| | - Shian-Shiang Wang
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taiwan; Institute of Medicine, Chung Shan Medical University, Taiwan; Department of Applied Chemistry, National Chi Nan University, Taiwan
| | - Chao-Yuan Huang
- Department of Urology, National Taiwan University Hospital, Taiwan; College of Medicine, National Taiwan University, Taiwan.
| | - See-Tong Pang
- Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan; Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou Branch, Taiwan.
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24
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Gogola S, Rejzer M, Bahmad HF, Alloush F, Omarzai Y, Poppiti R. Anti-Cancer Stem-Cell-Targeted Therapies in Prostate Cancer. Cancers (Basel) 2023; 15:cancers15051621. [PMID: 36900412 PMCID: PMC10000420 DOI: 10.3390/cancers15051621] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/21/2023] [Accepted: 03/04/2023] [Indexed: 03/09/2023] Open
Abstract
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men around the world. It is treated using a risk stratification approach in accordance with the National Comprehensive Cancer Network (NCCN) in the United States. The main treatment options for early PCa include external beam radiation therapy (EBRT), brachytherapy, radical prostatectomy, active surveillance, or a combination approach. In those with advanced disease, androgen deprivation therapy (ADT) is considered as a first-line therapy. However, the majority of cases eventually progress while receiving ADT, leading to castration-resistant prostate cancer (CRPC). The near inevitable progression to CRPC has spurred the recent development of many novel medical treatments using targeted therapies. In this review, we outline the current landscape of stem-cell-targeted therapies for PCa, summarize their mechanisms of action, and discuss avenues of future development.
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Affiliation(s)
- Samantha Gogola
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Michael Rejzer
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Correspondence: or ; Tel.: +1-305-674-2277
| | - Ferial Alloush
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Yumna Omarzai
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Robert Poppiti
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
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25
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Abdulfatah E, Fine SW, Lotan TL, Mehra R. Reprint of: de novo neuroendocrine features in prostate cancer. Hum Pathol 2023; 133:115-125. [PMID: 36894369 DOI: 10.1016/j.humpath.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 07/01/2022] [Indexed: 03/09/2023]
Abstract
Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.
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Affiliation(s)
- Eman Abdulfatah
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA
| | - Samson W Fine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21211, USA
| | - Rohit Mehra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, 48109, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, 48104, USA.
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26
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Gopalakrishnan S, Dhaware M, Sudharma AA, Mullapudi SV, Siginam SR, Gogulothu R, Mir IA, Ismail A. Chemopreventive Effect of Cinnamon and Its Bioactive Compounds in a Rat Model of Premalignant Prostate Carcinogenesis. Cancer Prev Res (Phila) 2023; 16:139-151. [PMID: 36517462 DOI: 10.1158/1940-6207.capr-22-0327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/21/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Cinnamon and its bioactive compounds inhibit prostate cancer cell proliferation in vitro. The aim of the current study was to assess the chemopreventive efficacy of cinnamon (CN) and its bioactive compounds in vivo using N-methyl-N-nitrosourea (MNU) and testosterone (T) to induce prostate carcinogenesis in male Wistar/National Institute of Nutrition rats. Cancer-induced (CI) rats (n = 10) developed prostatic hyperplasia and prostatic intraepithelial neoplasia. These histopathologic changes were diminished in CI rats fed for 4 months with diets supplemented with either CN (n = 20) or its bioactive compounds (cinnamaldehyde, n = 10 and procyanidin B2, n = 10). Androgen receptor (AR) expression was lower in the prostates of CI rats than in control, but the AR target gene, probasin, was robustly upregulated. Treatment of CI rats with CN or its bioactive compounds upregulated AR expression but inhibited the expression of the 5-alpha reductase genes (Srd5a1 and Srd5a2) and did not further increase probasin expression, suggesting blunted transcriptional activity of AR due to the limited availability of dihydrotestosterone. MNU+T induced an altered oxidant status in rat prostate, which was reflected by an increase in lipid peroxidation and DNA oxidation. These changes were completely or partially corrected by treatment with CN or the bioactive compounds. CN and its active components increased the activity of the apoptotic enzymes caspase-8 and caspase-3 in the prostates of CI rats. In conclusion, our data demonstrate that CN and its bioactive compounds have inhibitory effects on premalignant prostate lesions induced by MNU + T and, therefore, may be considered for the chemoprevention of prostate cancer. PREVENTION RELEVANCE The research work presented in this article demonstrates the chemopreventive efficacy of CN and its bioactive compounds in a rat model of premalignant prostate cancer.
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Affiliation(s)
- Srividya Gopalakrishnan
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India
| | - Mahamaya Dhaware
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India
| | | | | | | | - Ramesh Gogulothu
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India
| | - Irfan Ahmad Mir
- ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, Telangana, India
| | - Ayesha Ismail
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India
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27
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Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia. Curr Issues Mol Biol 2023; 45:1536-1567. [PMID: 36826044 PMCID: PMC9954984 DOI: 10.3390/cimb45020099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum (syn. Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri. Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others.
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28
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Cai P, Tang S, Xia L, Wang Y, Liu Y, Feng Y, Liu N, Chen Y, Zhou Z. Improve the Biodistribution with Bulky and Lipophilic Modification Strategies on Lys-Urea-Glu-Based PSMA-Targeting Radiotracers. Mol Pharm 2023; 20:1435-1446. [PMID: 36696174 DOI: 10.1021/acs.molpharmaceut.2c01101] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Since prostate-specific membrane antigen (PSMA) is upregulated in nearly all stages of prostate cancer (PCa), PSMA can be considered a viable diagnostic biomarker and treatment target in PCa. In this study, we have developed five 68Ga-labeled PSMA-targeted tracers, 68Ga-Flu-1, 68Ga-Flu-2, 68Ga-9-Ant, 68Ga-1-Nal, and 68Ga-1-Noi, to investigate the effect of lipophilic bulky groups on the pharmacokinetics of PSMA inhibitors compared to 68Ga-PSMA-11 and then explore their in vitro and in vivo properties. 68Ga-labeled PSMA inhibitors were obtained in 88.53-99.98% radiochemical purity and at the highest specific activity of up to 20 MBq/μg. These compounds revealed a highly efficient uptake and internalization into LNCaP cells and increased over time. PET imaging and biodistribution studies were performed in mice bearing PSMA expressing LNCaP prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The biodistribution studies showed that all these radioligands were excreted mainly via the renal pathway. The in vivo biodistribution of 68Ga-Flu-1 revealed higher tumor uptake (40.11 ± 9.24 %ID/g at 2 h p.i.) compared to 68Ga-PSMA-11 (28.10 ± 5.96 %ID/g at 2 h p.i.). Both in vitro and in vivo experiments showed that chemical modification of the lysine fragment significantly impacts tumor-targeting and pharmacokinetic properties. Great potential to serve as new PET tracers for prostate cancer has been revealed with these radiotracers─68Ga-Flu-1 in particular.
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Affiliation(s)
- Ping Cai
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Sufan Tang
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Li Xia
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Yinwen Wang
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Yang Liu
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Yue Feng
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Nan Liu
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Yue Chen
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
| | - Zhijun Zhou
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou 646000, Sichuan, China.,Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China.,Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou 646000, Sichuan, China
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Ploussard G, Rozet F, Roubaud G, Stanbury T, Sargos P, Roupret M. Chromogranin A: a useful biomarker in castration-resistant prostate cancer. World J Urol 2023; 41:361-369. [PMID: 36527470 PMCID: PMC9947027 DOI: 10.1007/s00345-022-04248-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
PURPOSE The natural history of prostate cancer (PC) almost always evolves to castration-resistant prostate cancer (CRPC) status, sometimes comprising pure or mixed neuroendocrine prostate cancers (NEPC) differentiation. In CRPC, monitoring using only prostate-specific antigen (PSA) is not optimal since neuroendocrine differentiated cells do not secrete PSA. Thus, monitoring with PSA and chromogranin A (CgA) may be useful. This review aims to evaluate evidence for the usefulness of CgA assessments during the monitoring of prostate cancer. METHOD This review was based on three recent meta-analysis concerning CgA and prostate cancer. Further data were obtained from PubMed and Embase databases by searches using keywords, including chromogranin A and prostate cancer. RESULTS CgA levels remain largely unchanged during the early PC evolution. The development of NEPC is characterised by lower PSA secretion and increased CgA secretion. Data supporting the prognostic value of high CgA baseline levels for survival are contrasting and scarce. However, increasing CgA levels early during treatment of metastatic (m)CRPC suggests resistance to treatment and predicts shorter survival, particularly in men with high baseline levels of CgA levels. In men with mCRPC, the first-line chemotherapy may be more appropriate than other agents when baseline CgA levels are high. Also, increasing CgA levels during treatment may indicate disease progression and may warrant a change of therapy. CONCLUSION CgA monitoring at baseline and regularly during mCRPC management may be useful for monitoring disease evolution. An increased CgA baseline levels and increasing CgA levels may assist physicians with choosing and modifying therapy.
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Affiliation(s)
- Guillaume Ploussard
- Department of Urology, Clinique La Croix du Sud, Quint-Fonsegrives, Institut Universitaire du Cancer de Toulouse (IUCT-O), Toulouse, France.
| | | | - Guilhem Roubaud
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | | | - Paul Sargos
- Department of Radiotherapy, Institut Bergonié, Bordeaux, France
| | - Morgan Roupret
- GRC 5 Predictive Onco-Uro, AP-HP, Urology, Pitié-Salpêtrière Hospital, Sorbonne University, 75013, Paris, France
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30
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Miller KJ, Henry I, Maylin Z, Smith C, Arunachalam E, Pandha H, Asim M. A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer. Front Oncol 2023; 13:1129140. [PMID: 36937454 PMCID: PMC10014620 DOI: 10.3389/fonc.2023.1129140] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.
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Affiliation(s)
| | | | - Zoe Maylin
- *Correspondence: Zoe Maylin, ; Mohammad Asim,
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31
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Cardoso HJ, Figueira MI, Carvalho TM, Serra CD, Vaz CV, Madureira PA, Socorro S. Androgens and low density lipoprotein-cholesterol interplay in modulating prostate cancer cell fate and metabolism. Pathol Res Pract 2022; 240:154181. [PMID: 36327818 DOI: 10.1016/j.prp.2022.154181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/16/2022] [Indexed: 11/15/2022]
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32
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Alamiri J, Britton CJ, Ahmed ME, Andrews JR, Higa JL, Dundar A, Karnes RJ, Kwon E, Lowe VJ, Kendi AT, Bold MS, Pagliaro LC. Radiographic paradoxical response in metastatic castrate-resistant prostate cancer (mCRPC) managed with new generation anti-androgens: a retrospective analysis. Prostate 2022; 82:1483-1490. [PMID: 36089822 DOI: 10.1002/pros.24413] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/11/2022] [Accepted: 06/21/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Prostatic specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration-resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti-androgens (SGA) post-chemotherapy using combined conventional imaging, and new generation imaging in the form of C-11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan. METHODS We retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3-6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C-11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging. RESULTS We identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75-21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group-A), whereas 39.6% displayed a paradoxical response (PR) (Group-B), defined as increased choline avidity combined with stable or down-trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group-A, 4.6 for Group-B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group-A versus Group-B, respectively (Log-Rank = 0.0063). CONCLUSION Nearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C-11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.
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Affiliation(s)
- Jamal Alamiri
- Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Mohamed E Ahmed
- Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jack R Andrews
- Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
| | - Julianna L Higa
- Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayca Dundar
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Eugene Kwon
- Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
| | - Val J Lowe
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayse T Kendi
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael S Bold
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Lance C Pagliaro
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
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33
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JAG1 Intracellular Domain Enhances AR Expression and Signaling and Promotes Stem-like Properties in Prostate Cancer Cells. Cancers (Basel) 2022; 14:cancers14225714. [PMID: 36428807 PMCID: PMC9688638 DOI: 10.3390/cancers14225714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/01/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found that JICD overexpression increased the expression levels of AR, especially AR-Vs, in PC cell lines and significantly enhanced androgen-independent and androgen-dependent function of ARs. Interestingly, JICD overexpression upregulated the expression of the PCSC marker CD133 in PC cells as the expression of self-renewal markers; namely, NANOG and OCT3/4 increased. In addition, JICD overexpression highly increased the expression of anti-apoptotic BCL-XL protein, while it little affected the expression of apoptotic BIM protein. In 3D cell culture assays, the spheres formed by JICD-overexpressing PC subline cells (C4-2 and CWR22Rv1) were larger than those formed by control (EV) subline cells with undifferentiated morphology. Although JICD overexpression caused quiescence in cell proliferation, it activated the expression of components in PCSC-related signaling pathways, increased PC cell mobility, and promoted in vivo xenograft mouse tumorigenesis. Therefore, JICD may play a crucial role in enhancing androgen independence and promoting stem-like properties in PC cells and should be considered a novel target for CRPC and PCSC diagnostic therapy.
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Marklund M, Schultz N, Friedrich S, Berglund E, Tarish F, Tanoglidi A, Liu Y, Bergenstråhle L, Erickson A, Helleday T, Lamb AD, Sonnhammer E, Lundeberg J. Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones. Nat Commun 2022; 13:5475. [PMID: 36115838 PMCID: PMC9482614 DOI: 10.1038/s41467-022-33069-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors.
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Affiliation(s)
- Maja Marklund
- Department of Gene Technology, KTH Royal Institute of Technology, Science for Life Laboratory, Solna, Sweden
| | - Niklas Schultz
- Division of Translational Medicine & Chemical Biology, Karolinska Institute, Science for Life Laboratory, Solna, Sweden
| | - Stefanie Friedrich
- Department of Biochemistry and Biophysics, Stockholm University, Science for Laboratory, Solna, Sweden
| | - Emelie Berglund
- Department of Gene Technology, KTH Royal Institute of Technology, Science for Life Laboratory, Solna, Sweden
| | - Firas Tarish
- Division of Translational Medicine & Chemical Biology, Karolinska Institute, Science for Life Laboratory, Solna, Sweden
| | - Anna Tanoglidi
- Department of Pathology, Evangelismos General Hospital, 45-47 Ipsilantou str, Athens, Greece
| | - Yao Liu
- Division of Translational Medicine & Chemical Biology, Karolinska Institute, Science for Life Laboratory, Solna, Sweden
| | - Ludvig Bergenstråhle
- Department of Gene Technology, KTH Royal Institute of Technology, Science for Life Laboratory, Solna, Sweden
| | - Andrew Erickson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Thomas Helleday
- Division of Translational Medicine & Chemical Biology, Karolinska Institute, Science for Life Laboratory, Solna, Sweden
| | - Alastair D Lamb
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Erik Sonnhammer
- Department of Biochemistry and Biophysics, Stockholm University, Science for Laboratory, Solna, Sweden.
| | - Joakim Lundeberg
- Department of Gene Technology, KTH Royal Institute of Technology, Science for Life Laboratory, Solna, Sweden.
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35
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Li Y, Song J, Zhou P, Zhou J, Xie S. Targeting Undruggable Transcription Factors with PROTACs: Advances and Perspectives. J Med Chem 2022; 65:10183-10194. [PMID: 35881047 DOI: 10.1021/acs.jmedchem.2c00691] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Dysregulation of transcription factors has been implicated in a variety of human diseases. However, these proteins have traditionally been regarded as undruggable and only a handful of them have been successfully targeted by conventional small molecules. Moreover, the development of intrinsic and acquired resistance has hampered the clinical use of these agents. Over the past years, proteolysis-targeting chimeras (PROTACs) have shown great promise because of their potential for overcoming drug resistance and their ability to target previously undruggable proteins. Indeed, several small molecule-based PROTACs have demonstrated superior efficacy in therapy-resistant metastatic cancers. Nevertheless, it remains challenging to identify ligands for the majority of transcription factors. Given that transcription factors recognize short DNA motifs in a sequence-specific manner, multiple novel approaches exploit DNA motifs as warheads in PROTAC design for the degradation of aberrant transcription factors. These PROTACs pave the way for targeting undruggable transcription factors with potential therapeutic benefits.
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Affiliation(s)
- Yan Li
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China
| | - Jian Song
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China
| | - Ping Zhou
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China
| | - Jun Zhou
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China.,State Key Laboratory of Medicinal Chemical Biology, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Songbo Xie
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China.,School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, China
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36
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Liu Y, Yu S, Xu T, Bodenko V, Orlova A, Oroujeni M, Rinne SS, Tolmachev V, Vorobyeva A, Gräslund T. Preclinical Evaluation of a New Format of 68Ga- and 111In-Labeled Affibody Molecule Z IGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT. Pharmaceutics 2022; 14:pharmaceutics14071475. [PMID: 35890370 PMCID: PMC9320461 DOI: 10.3390/pharmaceutics14071475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 02/04/2023] Open
Abstract
The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule ZIGF-1R:4551 binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the 68Ga and 111In-labeled affibody construct NODAGA-(HE)3-ZIGF-1R:4551 for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 ± 0.2 and 8.0 ± 0.6 for [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, respectively. In conclusion, a molecular design of the ZIGF-1R:4551 affibody molecule, including placement of a (HE)3-tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT.
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Affiliation(s)
- Yongsheng Liu
- Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden; (Y.L.); (T.X.); (M.O.); (A.V.)
| | - Shengze Yu
- Department of Protein Science, KTH Royal Institute of Technology, 10044 Stockholm, Sweden;
| | - Tianqi Xu
- Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden; (Y.L.); (T.X.); (M.O.); (A.V.)
| | - Vitalina Bodenko
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (V.B.); (A.O.)
| | - Anna Orlova
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (V.B.); (A.O.)
- Department of Medicinal Chemistry, Uppsala University, 75123 Uppsala, Sweden;
| | - Maryam Oroujeni
- Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden; (Y.L.); (T.X.); (M.O.); (A.V.)
- Affibody AB, 17165 Solna, Sweden
| | - Sara S. Rinne
- Department of Medicinal Chemistry, Uppsala University, 75123 Uppsala, Sweden;
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden; (Y.L.); (T.X.); (M.O.); (A.V.)
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (V.B.); (A.O.)
- Correspondence: (V.T.); (T.G.); Tel.: +46-704-250782 (V.T.); +46-8790-9627 (T.G.)
| | - Anzhelika Vorobyeva
- Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden; (Y.L.); (T.X.); (M.O.); (A.V.)
| | - Torbjörn Gräslund
- Department of Protein Science, KTH Royal Institute of Technology, 10044 Stockholm, Sweden;
- Correspondence: (V.T.); (T.G.); Tel.: +46-704-250782 (V.T.); +46-8790-9627 (T.G.)
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Phloretin in Benign Prostate Hyperplasia and Prostate Cancer: A Contemporary Systematic Review. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071029. [PMID: 35888117 PMCID: PMC9322491 DOI: 10.3390/life12071029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/02/2022] [Accepted: 07/09/2022] [Indexed: 11/16/2022]
Abstract
Currently, medication for benign prostate hyperplasia (BPH) and prostate cancer (PCa) are mainly based on modulating the hormone and nervous systems. However, side effects often affect patients, and might decrease their commitment to continuing the medication and lower their quality of life. Some studies have indicated that chronic inflammation might be the cause of BPH and PCa. Based on this hypothesis, the effect of phloretin, a potent anti-inflammatory and anti-oxidative flavonoid, has been researched since 2010. Results from animal and in-vitro studies, obtained from databases, also indicate that the use of phloretin in treating BPH and PCa is promising. Due to its effect on inflammatory cytokines, apoptosis or anti-apoptosis, reactive oxygen species, anti-oxidant enzymes and oxidative stress, phloretin is worthy of further study in human clinical trials regarding safety and effective dosages.
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Abdulfatah E, Fine SW, Lotan T, Mehra R. De Novo Neuroendocrine Features in Prostate Cancer. Hum Pathol 2022; 127:112-122. [PMID: 35810832 DOI: 10.1016/j.humpath.2022.07.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 07/01/2022] [Indexed: 12/22/2022]
Abstract
Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.
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Affiliation(s)
- Eman Abdulfatah
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Samson W Fine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tamara Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Rohit Mehra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
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TR3 Enhances AR Variant Production and Transactivation, Promoting Androgen Independence of Prostate Cancer Cells. Cancers (Basel) 2022; 14:cancers14081911. [PMID: 35454821 PMCID: PMC9031921 DOI: 10.3390/cancers14081911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/12/2022] [Accepted: 04/07/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Advanced prostate cancer development is associated with androgen-independent AR signaling. TR3 overexpression alters AR expression, splicing process, and transactivation towards increasing the androgen independence of AR signaling in prostate cancer cells. These results suggest that TR3 is a pivotal factor in the progression of prostate cancer to advanced form. Abstract The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively, although weakly, correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independence of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to an advanced castration-resistant form.
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Chen L, Sun Y, Tang M, Wu D, Xiang Z, Huang CP, You B, Xie D, Ye Q, Yu D, Chang C. High-dose-androgen-induced autophagic cell death to suppress the Enzalutamide-resistant prostate cancer growth via altering the circRNA-BCL2/miRNA-198/AMBRA1 signaling. Cell Death Dis 2022; 8:128. [PMID: 35318303 PMCID: PMC8941094 DOI: 10.1038/s41420-022-00898-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/07/2022] [Accepted: 02/14/2022] [Indexed: 01/22/2023]
Abstract
Androgen deprivation therapy (ADT) is a gold standard treatment for advanced PCa. However, most patients eventually develop the castration-resistant prostate cancer (CRPC) that progresses rapidly despite ongoing systemic androgen deprivation. While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients, the exact mechanism of this opposite effect remains unclear. Here we found that Enzalutamide-resistant (EnzR) CRPC cells can be suppressed by the high-dose-androgen (dihydrotestosterone, DHT). Mechanism dissection suggested that a high-dose-DHT can suppress the circular RNA-BCL2 (circRNA-BCL2) expression via transcriptional regulation of its host gene BCL2. The suppressed circRNA-BCL2 can then alter the expression of miRNA-198 to modulate the AMBRA1 expression via direct binding to the 3′UTR of AMBRA1 mRNA. The consequences of high-dose-DHT suppressed circRNA-BCL2/miRNA-198/AMBRA1 signaling likely result in induction of the autophagic cell death to suppress the EnzR CRPC cell growth. Preclinical studies using in vivo xenograft mouse models also demonstrated that AMBRA1-shRNA to suppress the autophagic cell death can weaken the effect of high-dose-DHT on EnzR CRPC tumors. Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future.
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Affiliation(s)
- Lei Chen
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China.,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Yin Sun
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Min Tang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.,Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Denglong Wu
- Department of Urology, Tongji Hospital, School of Medicine, Tongji Universiry, Shanghai, 200092, China
| | - Zhendong Xiang
- Department of Urology, Tongji Hospital, School of Medicine, Tongji Universiry, Shanghai, 200092, China
| | - Chi-Ping Huang
- Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan, ROC
| | - Bosen You
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Dongdong Xie
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China
| | - Qinglin Ye
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China
| | - Dexin Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China.
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. .,Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan, ROC.
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41
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Miller KJ, Asim M. Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer. Cells 2022; 11:cells11060952. [PMID: 35326402 PMCID: PMC8946764 DOI: 10.3390/cells11060952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023] Open
Abstract
The androgen receptor (AR) signalling pathway is the key driver in most prostate cancers (PCa), and is underpinned by several kinases both upstream and downstream of the AR. Many popular therapies for PCa that target the AR directly, however, have been circumvented by AR mutation, such as androgen receptor variants. Some upstream kinases promote AR signalling, including those which phosphorylate the AR and others that are AR-regulated, and androgen regulated kinase that can also form feed-forward activation circuits to promotes AR function. All of these kinases represent potentially druggable targets for PCa. There has generally been a divide in reviews reporting on pathways upstream of the AR and those reporting on AR-regulated genes despite the overlap that constitutes the promotion of AR signalling and PCa progression. In this review, we aim to elucidate which kinases—both upstream and AR-regulated—may be therapeutic targets and require future investigation and ongoing trials in developing kinase inhibitors for PCa.
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42
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Yin S, Chen Y, Tong H, Li T, Qin Z, Zhu J, He W. PP2A promotes apoptosis and facilitates docetaxel sensitivity via the PP2A/p‑eIF4B/XIAP signaling pathway in prostate cancer. Oncol Lett 2022; 23:101. [PMID: 35154432 PMCID: PMC8822497 DOI: 10.3892/ol.2022.13221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022] Open
Abstract
Serine/threonine protein phosphatase 2A (PP2A) is a protein that has a wide range of biological functions. As prostate cancer progresses from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC), the expression level of PP2A has been found to decrease. The present study aimed to determine the roles that PP2A may play in prostate cancer and its association with the downstream factor, X-linked inhibitor of apoptosis (XIAP). First, the mRNA and protein expression levels of PP2A in LNCaP, DU145 and PC-3 prostate cancer cell lines were measured. Next, the population of PP2A heterodimers was increased using a PP2A agonist, DT061, in the DU145 and PC-3 cell lines. PP2A expression was then knocked down in the LNCaP cell line. Western blot analysis was performed to determine the association between PP2A, phosphorylated (p)-eukaryotic initiation factor 4B (eIF4B) and XIAP. The results revealed that following the increase in PP2A expression, the DU145 and PC-3 cell lines were more sensitive to docetaxel according to Cell Counting Kit-8 assays and had an increased apoptotic rate as assessed by flow cytometry. Conversely, following the transfection of small interfering (si)PP2A into the LNCaP cell line, the sensitivity to docetaxel decreased, as well as the apoptotic rate. In addition, following treatment with the PP2A agonist, DT061, PP2A expression was found to be significantly upregulated, while p-eIF4B and XIAP protein expression levels were significantly downregulated. By contrast, following the transfection of siPP2A into the LNCaP cell line, PP2A protein expression levels were found to be downregulated, while p-eIF4B and XIAP expression levels were significantly upregulated. In conclusion, by affecting the downstream factor XIAP, PP2A may play a key role in promoting apoptosis and facilitating docetaxel sensitivity in prostate cancer cell lines.
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Affiliation(s)
- Siwen Yin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yong Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hang Tong
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tinghao Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zijia Qin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Junlong Zhu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Weiyang He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Wettstein L, Kirchhoff F, Münch J. The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment. Int J Mol Sci 2022; 23:1351. [PMID: 35163273 PMCID: PMC8836196 DOI: 10.3390/ijms23031351] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 01/25/2023] Open
Abstract
TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment.
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Affiliation(s)
| | | | - Jan Münch
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; (L.W.); (F.K.)
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44
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Epigenetic Coregulation of Androgen Receptor Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:277-293. [DOI: 10.1007/978-3-031-11836-4_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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45
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Jiang W, Wang X, Shu C, Hou Q, Yang K, Wu X. Design, synthesis, and evaluation of novel pyridone derivatives as potent BRD4 inhibitors for the potential treatment of prostate cancer. Bioorg Chem 2021; 119:105575. [PMID: 34995979 DOI: 10.1016/j.bioorg.2021.105575] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/17/2021] [Indexed: 12/14/2022]
Abstract
Since androgen receptor (AR) can bind to BRD4 protein and this binding can be blocked by BRD4 inhibitors, targeting BRD4 has emerged as a promising approach for the treatment of prostate cancer (PC). Herein, we designed and synthesized a series of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one derivatives as novel BRD4 inhibitors for prostate cancer. Among them, compound 13 displayed the most robust BRD4 inhibitory activity with an IC50 value of 18 nM. Furthermore, 13 showed potent anti-proliferative activity against enzalutamide-resistant 22RV1 cells. The mechanism of action studies demonstrated that 13 induced cell apoptosis by regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. In addition, the c-Myc level was significantly reduced in 22RV1 cells on the western blot assay. These findings collectively suggested that compound 13 might find potential use for the treatment of prostate cancer.
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Affiliation(s)
- Wenhua Jiang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xiaohui Wang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Chengxia Shu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Qiangqiang Hou
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Kexin Yang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xiaoxing Wu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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Prognostic Impact of Sarcopenia in Patients with Metastatic Hormone-Sensitive Prostate Cancer. Cancers (Basel) 2021; 13:cancers13246345. [PMID: 34944964 PMCID: PMC8699789 DOI: 10.3390/cancers13246345] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022] Open
Abstract
The clinical value of sarcopenia has not been determined yet in metastatic hormone-sensitive prostate cancer (mHSPC). We retrospectively evaluated data of 70 consecutive patients with mHSPC receiving treatment with either early docetaxel (n = 42) or abiraterone acetate (n = 28) between July 2018 and April 2021. Skeletal muscle index was calculated from cross-sectional areas of skeletal muscle on baseline computed tomography (CT), defining sarcopenia as a skeletal muscle index of ≤52.4 cm2/m2. Failure-free survival (FFS), radiographic progression-free survival, and time to prostate-specific antigen (PSA) progression were estimated using the Kaplan-Meier method, and differences in survival probability were compared using the log-rank test. Cox proportional hazards regression analysis was conducted to identify the predictors of clinical outcomes. Patients with sarcopenia (n = 47) had shorter FFS than those without sarcopenia (n = 23) (median, 20.1 months vs. not reached; log-rank p < 0.001). Sarcopenia was independently associated with shorter FFS (hazard ratio (HR), 6.69; 95% confidence interval (CI), 1.57-28.49; p = 0.010) and time to PSA progression (HR, 12.91; 95% CI, 1.08-153.85; p = 0.043). In conclusion, sarcopenia is an independent prognostic factor for poor FFS and time to PSA progression in patients with mHSPC who receive early docetaxel or abiraterone acetate treatment.
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Haffner MC, Bhamidipati A, Tsai HK, Esopi DM, Vaghasia AM, Low JY, Patel RA, Guner G, Pham MT, Castagna N, Hicks J, Wyhs N, Aebersold R, De Marzo AM, Nelson WG, Guo T, Yegnasubramanian S. Phenotypic characterization of two novel cell line models of castration-resistant prostate cancer. Prostate 2021; 81:1159-1171. [PMID: 34402095 PMCID: PMC8460612 DOI: 10.1002/pros.24210] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/30/2021] [Accepted: 08/04/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of resistance mechanisms and the assessment of drugs for the treatment of castration-resistant prostate cancer. METHODS We generated two novel cell line models (LAPC4-CR and VCaP-CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA-seq) and proteomic analyses (SWATH-MS) to delineate expression differences between castration-sensitive and castration-resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models. RESULTS The two cell line derivatives LAPC4-CR and VCaP-CR showed castration-resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High-dose androgen treatment resulted in significant growth arrest of VCaP-CR but not in LAPC4-CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration-resistant LNCaP-abl cells revealed an expression signature of castration resistance. CONCLUSIONS The two novel cell line models LAPC4-CR and VCaP-CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.
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Affiliation(s)
- Michael C. Haffner
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Pathology, University of Washington, Seattle, WA, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Akshay Bhamidipati
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Harrison K. Tsai
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
| | - David M. Esopi
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Ajay M. Vaghasia
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Jin-Yih Low
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Radhika A. Patel
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Gunes Guner
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Hacettepe University Faculty of Medicine, Department of Pathology, Ankara, Turkey
| | - Minh-Tam Pham
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Nicole Castagna
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Jessica Hicks
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Nicolas Wyhs
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
| | - Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, ETH, Zürich, Switzerland
- Faculty of Science, University of Zürich, Zürich. Switzerland
| | - Angelo M. De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William G. Nelson
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tiannan Guo
- Department of Biology, Institute of Molecular Systems Biology, ETH, Zürich, Switzerland
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China
| | - Srinivasan Yegnasubramanian
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA
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Jacob A, Raj R, Allison DB, Myint ZW. Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies. Cancers (Basel) 2021; 13:5417. [PMID: 34771580 PMCID: PMC8582395 DOI: 10.3390/cancers13215417] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/21/2021] [Accepted: 10/27/2021] [Indexed: 11/17/2022] Open
Abstract
Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.
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Affiliation(s)
- Aasems Jacob
- Department of Medicine, Division of Hematology & Oncology, Pikeville Medical Center, Pikeville, KY 41501, USA;
| | - Rishi Raj
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Pikeville Medical Center, Pikeville, KY 41501, USA;
| | - Derek B. Allison
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA;
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA
- Department of Urology, University of Kentucky, Lexington, KY 40536, USA
| | - Zin W. Myint
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA;
- Department of Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY 40536, USA
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van der Zande K, Oyen WJG, Zwart W, Bergman AM. Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation. Cancers (Basel) 2021; 13:cancers13174346. [PMID: 34503156 PMCID: PMC8431634 DOI: 10.3390/cancers13174346] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is an alpha-emitting radiopharmaceutical treatment for patients with metastatic castration resistant prostate cancer (mCRPC) with predominantly bone metastases. While responses to chemotherapeutic and antihormonal mCRPC treatments can be assessed by serum PSA levels, a decrease of serum PSA levels is not expected during Ra-223 therapy. Moreover, radiographic evaluation of bone metastases response is challenging. Therefore, novel biomarkers to select patients for Ra-223 treatment and monitoring response are urgently needed. In this review, we discuss the currently used and exploratory biomarkers for this purpose, including soluble and cellular factors detected in the peripheral blood, genetic defects and radiographic assessments. We conclude that some biomarkers, including metabolic products of collagen degradation and novel PET scan techniques, might hold promise as predictors of response to Ra-223 treatment. However, these biomarkers have not been extensively studied. Consequently, currently, no biomarker has established a place in patient stratification and response evaluation. Abstract Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers.
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Affiliation(s)
- Kim van der Zande
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Wim J. G. Oyen
- Department of Nuclear Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The Netherlands;
| | - Wilbert Zwart
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
- Correspondence: (W.Z.); (A.M.B.); Tel.: +31-2051-28156 (W.Z.); +31-2051-22569 (A.M.B.)
| | - Andries M. Bergman
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Correspondence: (W.Z.); (A.M.B.); Tel.: +31-2051-28156 (W.Z.); +31-2051-22569 (A.M.B.)
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Jillson LK, Yette GA, Laajala TD, Tilley WD, Costello JC, Cramer SD. Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes. Cancers (Basel) 2021; 13:3272. [PMID: 34208794 PMCID: PMC8269091 DOI: 10.3390/cancers13133272] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 12/20/2022] Open
Abstract
While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.
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Affiliation(s)
- Lauren K. Jillson
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.L.); (G.A.Y.); (T.D.L.); (J.C.C.)
| | - Gabriel A. Yette
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.L.); (G.A.Y.); (T.D.L.); (J.C.C.)
| | - Teemu D. Laajala
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.L.); (G.A.Y.); (T.D.L.); (J.C.C.)
- Department of Mathematics and Statistics, University of Turku, 20500 Turku, Finland
| | - Wayne D. Tilley
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia;
- Freemason’s Foundation Centre for Men’s Health, University of Adelaide, Adelaide, SA 5005, Australia
| | - James C. Costello
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.L.); (G.A.Y.); (T.D.L.); (J.C.C.)
| | - Scott D. Cramer
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.L.); (G.A.Y.); (T.D.L.); (J.C.C.)
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