scholarly journals Activin A Stimulates AKR1C3 Expression and Growth in Human Prostate Cancer

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5726-5734 ◽  
Author(s):  
Johannes Hofland ◽  
Wytske M. van Weerden ◽  
Jacobie Steenbergen ◽  
Natasja F. J. Dits ◽  
Guido Jenster ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Activin A ◽  
High Ratio ◽  
Enzyme Expression ◽  
Steroidogenic Enzyme ◽  
Expression Levels ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Dehydrogenase Enzyme ◽  
Xenograft Models

Abstract Local androgen synthesis in prostate cancer (PC) may contribute to the development of castration-resistant PC (CRPC), but pathways controlling intratumoral steroidogenic enzyme expression in PC are unknown. We investigated the effects of activin, a factor involved in the regulation of PC growth and steroidogenic enzyme expression in other steroidogenic tissues, on intratumoral steroidogenesis in PC. Activin A effects and regulation of the activin-signaling pathway molecules were studied in the PC cell lines LNCaP, VCaP, and PC-3 and in 13 individual PC xenograft models. Also, expression levels of inhibin βA- and βB-subunits (INHBA and INHBB) and of the activin antagonist follistatin were quantitated in patient PC tissues. Activin A induced the expression and enzyme activity of 17β-hydroxysteroid dehydrogenase enzyme AKR1C3 in LNCaP and VCaP cells. Inhibition of endogenous activin A action in the PC-3 cell line decreased AKR1C3 levels and consequently testosterone synthesis. In return, androgens suppressed INHBA expression in both VCaP cells and the PC xenograft models. The antiproliferative effects of activin A were opposed by physiological concentrations of androstenedione in LNCaP cells. In patient PC tissues, expression levels of INHBA were increased in CRPC samples and correlated with AKR1C3 levels. Moreover, a high ratio of activin subunits to follistatin was associated with a worse metastasis-free survival in patients. In conclusion, activin A is controlled by androgens in PC models and regulates local androgen production. Activin A thus seems to mediate (residual) intratumoral androgen levels and could form a novel therapeutic target in CRPC.

scholarly journals Treatment characteristics for nonmetastatic castration-resistant prostate cancer in the United States, Europe and Japan

2019 ◽  
Vol 15 (35) ◽  
pp. 4069-4081 ◽  
Author(s):  
Ruchitbhai Shah ◽  
Marc Botteman ◽  
Reginald Waldeck
Keyword(s):  
Prostate Cancer ◽  
Eastern Cooperative Oncology Group ◽  
Patient Characteristics ◽  
The United States ◽  
Treatment Patterns ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
The Us ◽  
Androgen Synthesis Inhibitors

Aim: We conducted this study to describe nonmetastatic castration-resistant prostate cancer (nmCRPC) patient characteristics and treatment patterns in the US, Europe and Japan. Materials & methods: Descriptive analyses were conducted using the 2015–2017 Ipsos Global Oncology Monitor Database. Results: A total of 2065 (442 in the US, 509 in Europe and 1114 in Japan) patients (median age: 74–80 years; stage III at diagnosis : 38.5%; Eastern Cooperative Oncology Group [ECOG] score ≤1: 79.4%; treated by urologist : 88.4%) were included in the analytic cohort. Luteinizing hormone-releasing hormone agonists and antiandrogens were the most commonly used first regimen treatments. With subsequent nmCRPC regimens their use decreased, while the use of chemotherapy, corticosteroids, androgen synthesis inhibitors and second-generation androgen receptor inhibitors increased. Conclusion: These data represent real-world treatment patterns in nmCRPC.

Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically

2011 ◽  
Vol 29 (27) ◽  
pp. 3651-3658 ◽  
Author(s):  
Charles J. Ryan ◽  
Donald J. Tindall
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Clinical Success ◽  
Abiraterone Acetate ◽  
Clinical Findings ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant

Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen–androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, along with other similar therapies, confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease. Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way. The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling, even in the castrate state.

scholarly journals Minireview: Androgen Metabolism in Castration-Resistant Prostate Cancer

2013 ◽  
Vol 27 (5) ◽  
pp. 708-714 ◽  
Author(s):  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Synthesis Inhibitor ◽  
Androgen Independence ◽  
Androgen Synthesis ◽  
Androgen Receptor Antagonist ◽  
Castration Resistant ◽  
Hormonal Therapies ◽  
Additional Clinical Benefit

Abstract The decades-old terminology of androgen independence has been replaced in recent years with castration-resistant prostate cancer. Biological and clinical evidence have together conspired to support the use of this revised terminology by demonstrating that in the vast majority of cases tumors are neither truly depleted of androgens, nor are they free of the requirement for androgens to sustain growth and progression. Abiraterone acetate, an androgen synthesis inhibitor, and enzalutamide, a potent androgen receptor antagonist, both exploit the continued requirement for androgens. A central question, given the therapeutic gains enabled by further suppression of the androgen axis with these newer agents, is whether there may be additional clinical benefit gained by moving the goal posts of androgen suppression even further. The answer lies in part with the mechanisms utilized by tumors that enable resistance to these therapies. The aims of this review were to give a broad outline of steroidogenesis in prostate cancer and to highlight recent developments in understanding resistance to hormonal therapies.

scholarly journals Genetic characterization of a mouse line with primary aldosteronism

2017 ◽  
Vol 58 (2) ◽  
pp. 67-78 ◽  
Author(s):  
L G Perez-Rivas ◽  
Y Rhayem ◽  
S Sabrautzki ◽  
C Hantel ◽  
B Rathkolb ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Primary Aldosteronism ◽  
Point Mutations ◽  
Mouse Line ◽  
Enzyme Expression ◽  
Steroidogenic Enzyme ◽  
Knock Out ◽  
Expression Levels ◽  
To Come ◽  
Aldosterone To Renin Ratio

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.

scholarly journals LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Qiuhui Li ◽  
Bigang Liu ◽  
Hsueh-Ping Chao ◽  
Yibing Ji ◽  
Yue Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Development ◽  
Dependent Manner ◽  
Oncogenic Signaling ◽  
Transgenic Expression ◽  
Functional Studies ◽  
Castration Resistant ◽  
A Cell ◽  
Xenograft Models

AbstractLRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 is overexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR+ and AR− xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites in LRIG1 locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.

scholarly journals Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

2020 ◽  
Vol 21 (15) ◽  
pp. 5484 ◽  
Author(s):  
Tae Jin Kim ◽  
Kyo Chul Koo
Keyword(s):  
Prostate Cancer ◽  
Solid Tumors ◽  
Treatment Modality ◽  
Cytotoxic Agents ◽  
Therapeutic Modality ◽  
Current Status ◽  
Molecular Diagnostic ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against cancer cells shows potential as a therapeutic modality for various solid tumors and hematologic malignancies. With technological advances over the last decade, immunotherapy has become an integral treatment modality for advanced solid tumors. The feasibility of immunotherapy has shown promise for patients with PCa, and with advances in molecular diagnostic platforms and our understanding of immune mechanisms, immunotherapy is reemerging as a potential treatment modality for PCa. Various combinations of individualized immunotherapy and immune checkpoint blockers with androgen receptor-targeted therapies and conventional cytotoxic agents show promise. This article will review the current status of immunotherapy, including new discoveries and precision approaches to PCa, and discuss future directions in the continuously evolving landscape of immunotherapy.

scholarly journals Consequences of Different Corticosteroids on Serum Potassium and Prostate-Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study

2017 ◽  
Vol 11 ◽  
pp. 117955491773773 ◽  
Author(s):  
Masaomi Tatsuzawa ◽  
Ryuichi Ogawa ◽  
Naoki Kinjo ◽  
Soan Kim ◽  
Fumitaka Shimizu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Serum Potassium ◽  
Medical Records ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Synthesis Inhibitor ◽  
Androgen Synthesis ◽  
Castration Resistant

Background: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. Methods: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records. Results: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. Conclusions: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.

Effect of thalidomide on the TGFβ-1-mediated synthesis of testosterone from DHEA in prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 141-141
Author(s):  
Tristan Sissung ◽  
C. Tyler Kirkland ◽  
Kelie M Reece ◽  
Julia T Arnold ◽  
William Douglas Figg
Keyword(s):  
Prostate Cancer ◽  
Stromal Cells ◽  
Angiogenesis Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
The Difference ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Testosterone Synthesis

141 Background: TGFβ-1 induces conversion of DHEA to testosterone in prostate cancer stromal cells. We hypothesized that thalidomide would inhibit TGFβ-1-mediated formation of testosterone from DHEA. Methods: We grew LAPC4 or LNCaP prostate cancer epithelial cells and 6S primary prostate stromal cells in mono-/co-culture with DHEA (100nM) and/or TGFβ-1 (40 or 100pM). Testosterone and PSA concentration in media were ascertained using ELISA and corrected for cell count using CCK8 (%DHEA controls). Results: TGFβ-1 and DHEA induced a dose-dependent increase in the formation of testosterone over controls (∼5-6 fold; P<0.0001). Thalidomide (100μM) inhibited the formation of testosterone in cocultured cells treated with DHEA and TGFβ-1 (40pM) by 35% (P=0.0008). The thalidomide analogues, CPS49 (10μM) and lenalidomide (10μM) also had activity; CPS49 inhibited testosterone synthesis by 54% (P=0.010) while lenalidomide reduced testosterone by 15% (P=0.011). However, only thalidomide and CPS49 decreased median PSA secretion (40% and 93% respectively; P≤0.031). Other angiogenesis inhibitors (i.e., suramin (10μM) and sorafenib (500pM)) had no effect on testosterone synthesis (P>0.05). Therefore, anti-androgen activity was not a class effect of antiangiogenesis agents. Ketoconazole also did not have activity suggesting that TGFβ-1-induced testosterone synthesis from DHEA evades standard therapies designed to inhibit androgen synthesis enzymes (i.e. CYP3A4 and CYP17 inhibitors). We assessed the phosphorylation status of TGFβ-1 pathway constituents (i.e., SMAD2/3, p38, JNK, and ERK) in cocultured cells treated as above. Thalidomide inhibits the phosphorylation of ERK without affecting total ERK levels; however, neither MEK inhibition (via U0126) nor Raf inhibition (via sorafenib) resulted in anti-androgenic effects in these cells suggesting that the canonical RAF/MEK/ERK pathway is not responsible for the difference in testosterone secretion phenotype. Conclusions: These results indicate that thalidomide and its analogues have anti-androgen activity and may explain the success of thalidomide and its analogues in clinical treatment of hormone-dependent and castration-resistant prostate cancer.

Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response in castration-resistant patients.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e583-e583
Author(s):  
Camilla Thellenberg Karlsson ◽  
Lee-ann Tjon-Kon-Fat ◽  
Marie Lundholm ◽  
Mona Schröder ◽  
Thomas Wurdinger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Best Practice ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Therapy Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Biomarker Analysis

e583 Background: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance. Methods: The isolated platelet population of blood samples and QRT-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis directed therapies. The association between biomarker status in platelets (positive vs. negative) and therapy response, progression-free survival (PFS) and overall survival (OS) was examined. Results: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-3 ( KLK3), androgen receptor splice-variant 7 (ARV7), folate hydrolase 1 (FOLH1), and neuropeptide-Y ( NPY) were present within the platelet fraction. Analyzing biomarkers in the chemotherapy group did not add information about PFS, but FOLH1 was associated with short OS (p = 0.00015). In the abiraterone treated cohort, detectable FOLH1 (p = 0.009), KLK3 (p = 0.018), and NPY (p = 0.028) were all associated with short PFS. Patients with biomarker-negative platelets had the best outcome, while FOLH1 and NPY provided independent predictive information regarding PFS and KLK3 (p = 0.001) and FOLH1 (p = 0.002) were associated with short OS. Conclusions: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with high accuracy. Platelet-based analysis of FOLH1, NPY, and KLK3 may be used for treatment stratification of patients scheduled for treatment with abiraterone.

Sign in / Sign up

Export Citation Format

Share Document