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 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.

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.

Treatment duration and utilization patterns in metastatic castration-resistant prostate cancer patients receiving enzalutamide or abiraterone acetate.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 229-229
Author(s):  
Vahan Kassabian ◽  
Scott Flanders ◽  
Samuel Wilson ◽  
Bruce A. Brown ◽  
Yan Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Duration ◽  
Index Date ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Utilization Patterns ◽  
The Difference ◽  
Hormonal Therapies

229 Background: Enzalutamide (ENZA) and abiraterone acetate (ABI) are approved hormonal therapies for men with metastatic castration-resistant prostate cancer (mCRPC). This study assessed real-world treatment duration and utilization patterns in patients receiving ENZA or ABI. Methods: Adult mCRPC patients initiating ENZA or ABI before or after cytotoxic chemotherapy were identified from the Truven MarketScan® claims database (2012–2015). The index date was the first initiation of ENZA or ABI; continuous insurance enrollment for ≥6 months prior to and ≥3 months after the index date was required. Treatment discontinuation was defined as a prescription gap of ≥45 days. Median treatment duration was estimated using Kaplan–Meier method. Treatment switching was defined as starting a new mCRPC-related therapy within 30 days before to 45 days after the discontinuation date. Analyses were separately conducted for chemo-naïve and chemo-experienced patients. Results: The study included 3230 chemo-naive (ENZA 920; ABI 2310) and 692 chemo-experienced patients (ENZA 262; ABI 430). Among chemo-naive patients, ENZA cohort was older (mean age 74.5 vs 73.5; p = 0.013), with a higher proportion of comorbidities vs ABI cohort. Treatment duration was longer for ENZA cohort than ABI cohort (log-rank p = 0.008; median = ENZA 10.7 vs ABI 8.8 months). Within 1 year of initiation, 55.7% of ENZA and 60.8% of ABI cohort discontinued treatment and 22.5% and 34.7%, respectively, switched to other mCRPC therapies. Results were consistent among subgroups with specific comorbidities. Treatment duration was shorter among chemo-experienced patients than chemo-naïve; the difference between ENZA vs ABI among chemo-experienced patients was not statistically significant (log-rank p = 0.255; median = ENZA 7.5 vs ABI 7.1 months). Conclusions: Despite a more complex profile at baseline, chemo-naive mCRPC patients in the ENZA cohort had a longer treatment duration and lower proportion of switching to other prostate-cancer-directed therapies vs the ABI cohort. The difference of treatment duration between the two cohorts was not statistically significant for chemo-experienced patients.

Study of cases of abiraterone discontinuation due to toxicity in pre-chemotherapy after 1 year’s experience

2016 ◽  
Vol 23 (8) ◽  
pp. 615-619 ◽  
Author(s):  
Luis Ramudo-Cela ◽  
Jesús Balea-Filgueiras ◽  
José Ramón Vizoso-Hermida ◽  
Isabel Martín-Herranz
Keyword(s):  
Prostate Cancer ◽  
Side Effects ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Irreversible Inhibitor ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Discontinuation Of Treatment ◽  
Early Phases

Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment.

Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven

2008 ◽  
Vol 26 (28) ◽  
pp. 4563-4571 ◽  
Author(s):  
Gerhardt Attard ◽  
Alison H.M. Reid ◽  
Timothy A. Yap ◽  
Florence Raynaud ◽  
Mitch Dowsett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Specific Antigen ◽  
Serum Testosterone ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Mineralocorticoid Receptor Antagonist ◽  
Androgen Synthesis ◽  
Castration Resistant

Purpose Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate—a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis—was pursued. Patients and Methods Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts. Results Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess—namely hypertension, hypokalemia, and lower-limb edema—were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen ≥ 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to ≥ 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented. Conclusion CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.

scholarly journals Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

2014 ◽  
Vol 21 (4) ◽  
pp. T87-T103 ◽  
Author(s):  
Kathryn E Ware ◽  
Mariano A Garcia-Blanco ◽  
Andrew J Armstrong ◽  
Scott M Dehm
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Hormonal Regulation ◽  
Clonal Selection ◽  
Resistance Mechanism ◽  
Biological Properties ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Hormonal Therapies

As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

scholarly journals KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dingheng Lu ◽  
Yarong Song ◽  
Ying Yu ◽  
Decai Wang ◽  
Bing Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcriptional Activity ◽  
Critical Role ◽  
Specific Antigen ◽  
Hormonal Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Post Translational Modification ◽  
Synthesis Inhibitor ◽  
Androgen Synthesis ◽  
Castration Resistant

AbstractAbiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.

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