scholarly journals Gonadotropin-Releasing Hormone Receptors in Prostate Cancer: Molecular Aspects and Biological Functions

2020 ◽  
Vol 21 (24) ◽  
pp. 9511
Author(s):  
Fabrizio Fontana ◽  
Monica Marzagalli ◽  
Marina Montagnani Marelli ◽  
Michela Raimondi ◽  
Roberta Moretti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Hormone Receptors ◽  
Early Stage ◽  
Disease Free Survival ◽  
Gonadotropin Releasing Hormone ◽  
Gnrh Agonists ◽  
Castration Resistant Prostate Cancer ◽  
Releasing Hormone ◽  
Reproductive Axis

Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials.

Recent Development and Future Prospects of Molecular Targeted Therapy in Prostate Cancer

2021 ◽  
Vol 14 ◽  
Author(s):  
Jinku Zhang ◽  
Jirui Sun ◽  
Sahar Bakht ◽  
Waseem Hassan
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Molecular Targeted Therapy ◽  
Abiraterone Acetate ◽  
Gonadotropin Releasing Hormone ◽  
Castration Resistant Prostate Cancer ◽  
Future Prospects ◽  
The Past ◽  
Castration Resistant ◽  
Previous Decade

: Prostate cancer (PC) is a rapidly increasing ailment worldwide. The previous decade has observed a rapid advancement in PC therapies that was evident from the number of FDA approvals during this phase. Androgen deprivation therapies (ADT) have traditionally remained a mainstay for the management of PCs, but the past decade has experienced the emergence of newer classes of drugs that can be used with or without the administration of ADT. FDA approved poly (ADP-ribose) polymerase inhibitors (PARPi), such as olaparib and rucaparib, after successful clinical trials against gene-mutated metastatic castration-resistant prostate cancer. Furthermore, drugs like apalutamide, darolutamide, and enzalutamide with an androgen-targeted mechanism of action have manifested superior results in non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), and metastatic castration-resistant prostate cancer (mCRPC), respectively, with or without previously administered docetaxel. Relugolix, an oral gonadotropin-releasing hormone antagonist, and a combination of abiraterone acetate plus prednisone were also approved by FDA after a successful trial in advanced PC and mCRPC, respectively. This review aims to analyze the FDA-approved agents in PC during the last decade and provide a summary of their clinical trials. It also presents an overview of the ongoing progress of prospective molecules still under trial.

The cardiovascular effects of gonadotropin-releasing hormone antagonists in men with prostate cancer

2021 ◽  
Author(s):  
Filipe Cirne ◽  
Nazanin Aghel ◽  
Jo-Anne Petropoulos ◽  
Laurence Klotz ◽  
Daniel J Lenihan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cardiovascular Events ◽  
Gnrh Antagonist ◽  
Cardiovascular Effects ◽  
Cardiovascular Death ◽  
Gonadotropin Releasing Hormone ◽  
Gnrh Agonists ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Gonadotropin Releasing Hormone Antagonists

Abstract Aims The aim of this study was to determine whether gonadotropin-releasing hormone (GnRH) antagonists (an emerging class of drugs to suppress testosterone synthesis in the treatment of prostate cancer) cause less adverse cardiovascular events than the more commonly use GnRH agonists. Methods and results We conducted a systematic review to identify all randomized, controlled trials in which a GnRH antagonist was compared with a GnRH agonist in men with prostate cancer. We identified 10 eligible studies including two different GnRH antagonists, degarelix (n = 1681) and relugolix (n = 734), which were compared with the GnRH agonists, leuprolide (n = 714) and goserelin (n = 600). The pooled risk ratios (95% confidence intervals) among GnRH antagonist recipients for adverse cardiovascular events, cardiovascular death, and all-cause mortality were 0.57 (0.39–0.81); 0.49 (0.25–0.96); and 0.48 (0.28–0.83), respectively. Important limitations of the included trials were their short duration of follow-up, unblinded study design and (in most of the studies) the identification of adverse cardiovascular events through safety reporting mechanisms rather than as a pre-specified outcome. There was no evidence of heterogeneity of findings among the studies. Conclusions There is consistent but methodologically limited data to suggest that GnRH antagonists—a relatively new class of androgen deprivation therapy for prostate cancer—cause significantly less cardiovascular adverse effects than the more frequently used GnRH agonists.

scholarly journals Recent Advances in the Management of Metastatic Prostate Cancer

2021 ◽  
pp. OP.21.00206
Author(s):  
Nicolas Sayegh ◽  
Umang Swami ◽  
Neeraj Agarwal
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Standard Of Care ◽  
Serum Testosterone ◽  
Gonadotropin Releasing Hormone ◽  
Novel Agents ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Releasing Hormone ◽  
Specific Membrane

Management of metastatic prostate cancer has undergone a revolution over the past decade with the introduction of several novel agents and repurposing of others. Several clinical trials reported improved outcomes with the intensification of androgen deprivation therapy by the addition of docetaxel chemotherapy or novel hormonal agents (abiraterone, enzalutamide, or apalutamide) in the metastatic castration-sensitive state. Relugolix has been recently approved as the first oral gonadotropin-releasing hormone receptor antagonist agent with a superior cardiovascular side-effect profile, and serum testosterone suppression compared with a gonadotropin-releasing hormone agonist, leuprolide. Poly-ADP ribose polymerase inhibitors (olaparib and rucaparib) have demonstrated significant clinical benefit for patients harboring deleterious mutations in genes belonging to the homologous recombination repair pathway and have received Food and Drug Administration approval. Recently, lutetium-177-prostate-specific membrane antigen-617 with standard of care treatment has shown to improve overall survival in men with advanced-stage prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer. These recent approvals, successes, and the ongoing investigation of multiple novel agents are expected to continue to dramatically improve survival outcomes of men with metastatic prostate cancer in the coming years.

Gonadotropin-Releasing Hormone Agonists and Fracture Risk: A Claims-Based Cohort Study of Men With Nonmetastatic Prostate Cancer

2005 ◽  
Vol 23 (31) ◽  
pp. 7897-7903 ◽  
Author(s):  
Matthew R. Smith ◽  
Won Chan Lee ◽  
Jane Brandman ◽  
Qin Wang ◽  
Marc Botteman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cohort Study ◽  
Relative Risk ◽  
Fracture Risk ◽  
Gnrh Agonist ◽  
Vertebral Fractures ◽  
Gonadotropin Releasing Hormone ◽  
Gnrh Agonists ◽  
Releasing Hormone ◽  
Clinical Fractures

Purpose Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density, a surrogate for fracture risk, in men with prostate cancer. We conducted a claims-based cohort study to characterize the relationship between GnRH agonists and risk for clinical fractures in men with nonmetastatic prostate cancer. Patients and Methods Using medical claims data from a 5% national random sample of Medicare beneficiaries, we identified a study group of men with nonmetastatic prostate cancer who initiated GnRH agonist treatment from 1992 to 1994 (n = 3,887). A comparison group of men with nonmetastatic prostate cancer who did not receive GnRH agonist treatment during the study period (n = 7,774) was matched for age, race, geographic location, and comorbidity. Clinical fractures were identified using inpatient, outpatient, and physician claims during 7 years of follow-up. Results In men with nonmetastatic prostate cancer, GnRH agonists significantly increased fracture risk. The rate of any clinical fracture was 7.88 per 100 person-years at risk in men receiving a GnRH agonist compared with 6.51 per 100 person-years in matched controls (relative risk, 1.21; 95% CI, 1.14 to 1.29; P < .001). Rates of vertebral fractures (relative risk, 1.45; 95% CI, 1.19 to 1.75; P < .001) and hip/femur fractures (relative risk, 1.30; 95% CI, 1.10 to 1.53; P = .002) were also significantly higher in men who received a GnRH agonist. GnRH agonist treatment independently predicted fracture risk in multivariate analyses. Longer duration of treatment conferred greater fracture risk. Conclusion GnRH agonists significantly increase risk for any clinical fracture, hip fractures, and vertebral fractures in men with prostate cancer.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

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