Cornerstone Of Treatment For Prostate Cancer Research Articles

Glucocorticoid receptor action in prostate cancer: the role of transcription factor crosstalk.

Prostate cancer is one of the most prevalent malignancies and is primarily driven by aberrant androgen receptor (AR) signaling. While AR-targeted therapies form the cornerstone of prostate cancer treatment, they often inadvertently activate compensatory pathways, leading to therapy resistance. This resistance is frequently mediated through changes in transcription factor (TF) crosstalk, reshaping gene regulatory programs and ultimately weakening treatment efficacy. Consequently, investigating TF interactions has become crucial for understanding the mechanisms driving therapy-resistant cancers. Recent evidence has highlighted the crosstalk between the glucocorticoid receptor (GR) and AR, demonstrating that GR can induce prostate cancer therapy resistance by replacing the inactivated AR, thereby becoming a driver of the disease. In addition to this oncogenic role, GR has also been shown to act as a tumor suppressor in prostate cancer. Owing to this dual role and the widespread use of glucocorticoids as adjuvant therapy, it is essential to understand GR's actions across different stages of prostate cancer development. In this review, we explore the current knowledge of GR in prostate cancer, with a specific focus on its crosstalk with other TFs. GR can directly and indirectly interact with a variety of TFs, and these interactions vary significantly depending on the type of prostate cancer cells. By highlighting these crosstalk interactions, we aim to provide insights that can guide the research and development of new GR-targeted therapies to mitigate its harmful effects in prostate cancer.

(297) Evaluation of Endothelial Function and Metabolic Profile in Patients with Prostate Cancer Undergoing Androgen Deprivation Therapy

Abstract Introduction Androgen deprivation therapy (ADT) has been the cornerstone of prostate cancer treatment. ADT delays cancer progression, alleviates cancer-related symptoms, and is associated with survival gains. Despite these established benefits, the therapy comes with known side effects, such as increased cardiovascular adverse events and metabolic changes. Despite the well-established association between the level of circulating testosterone and endothelial integrity, the direct effects of ADT on endothelial function remain controversial. Objective The aim of the present study was to investigate the impact of ADT on endothelial function, through the analysis of vascular parameters of the brachial artery, and the measurement of serum inflammatory markers. It was also our goal to evaluate early impact of ADT on anthropometric and metabolic parameters Methods We prospectively evaluated men with moderate to high-risk prostate cancer treated with ADT from January to July 2022 at our institution. Patients with decompensated diabetes mellitus (HbA1c >9%), active smokers or smokers who have ceased for less than 5 years and those with confirmed diagnosis of peripheral artery disease, coronary artery disease, angina, congestive heart failure, myocardial infarction, coronary revascularization or stroke, were excluded. Brachial artery assessment included vascular diameter and flow-mediated (endothelium-dependent) vasodilation (FMD) using high-resolution B-mode ultrasound. Our metabolic and inflammatory profile included serum measurement of total cholesterol and fractions, triglycerides, fasting glucose, glycated hemoglobin, basal insulin, C-reactive protein, and bioimpedance assessment of body fat distribution. All measurements were performed at baseline and after 3 months of ADT initiation with goserelin acetate 10.80mg. Results A total of 14 men with mean age of 67.9 ± 6.9 years were included. The prevalence of diabetes in the present cohort was 21.4%. FMD demonstrated a slight increase following ADT, which did not reach statistical significance after 3 months (median 2.2% vs. 5.0%; p = 0.8224 – Figure 1). Baseline brachial artery diameter significantly decreased with ADT compared to baseline (median diameter 0.43cm vs 0.40cm; p = 0.006). With regard to the metabolic profile, ADT significantly increased insulin resistance: fasting insulin levels (mean 9.67 ± 6.09 vs 13.19 ± 7.47; p = 0.002), glycated hemoglobin (mean 5.79% ± 0.47 vs 6.22% ± 0.75; p = 0.009) and homeostatic model assessment insulin resistance increased significantly after 3 months (p = 0.006). Low-density lipoprotein cholesterol (mean 112.00 ± 27.35 vs 128.90 ± 29.00; p = 0.01) and triglycerides (mean 145.40 ± 78.52 vs 168.20 ± 105.80; p = 0.03) concentrations were higher after 3 months of ADT. No significant differences were found in body fat distribution. Conclusions Although the present study has not demonstrated a significant change in brachial artery FMD, we verified an important and surprisingly early worsening of the metabolic profile with ADT, especially increased insulin resistance and dyslipidemia, which represent well-established risk factors for cardiovascular events. Disclosure No

A Phase I Clinical Trial Evaluating the Safety and Dosing of Relugolix with Novel Hormonal Therapy for the Treatment of Advanced Prostate Cancer.

Androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, is commonly co-prescribed as combination therapy. To better understand the safety and tolerability profile of relugolix, an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, in combination with abiraterone acetate (abiraterone) and apalutamide, a phase I study was undertaken. This is an ongoing, 52-week, open-label, parallel cohort study of relugolix in combination with abiraterone in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) [Part 1] and apalutamide in men with mCSPC or non-metastatic castration-resistant prostate cancer (nmCRPC) [Part 2]. Eligible patients treated with leuprolide acetate or degarelix with abiraterone or apalutamide prior to baseline, at which time they were transitioned to relugolix. Assessments included reporting of adverse events, clinical laboratory tests, vital sign measurements, electrocardiogram (ECG) parameters, and testosterone serum concentrations. In this interim report, patients completing ≥12 weeks were included. Overall, 15 men were enrolled in Part 1 and 10 in Part 2. Adverse events were mostly mild-to-moderate in intensity and were consistent with the known safety profiles of the individual medications. No transition (from prior ADT treatment)- or time-related trends in clinical laboratory tests, vital sign measurements, or ECG parameters were observed. Mean testosterone concentrations remained below castration levels. Combination therapy of relugolix and abiraterone or apalutamide was associated with a favorable safety and tolerability profile consistent with the known profiles of the individual medications. Castration levels of testosterone were maintained after transitioning to relugolix from other ADTs. ClinicalTrials.gov identifier: NCT04666129.

Relugolix in combination with abiraterone acetate, apalutamide, or docetaxel in men with advanced prostate cancer (aPC): A phase 1, three-part, open-label, parallel-cohort study.

TPS207 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs or receptor antagonists is a cornerstone of prostate cancer treatment. As disease progresses, agents with complementary mechansims are co-prescribed with ADT to suppress extra-testicular testosterone production or block androgen receptors on cancer cells. Relugolix (120 mg) is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 study, relugolix maintained suppression of testosterone to castration levels in 96.7% of men for up to 48 weeks (wks), with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). To formally assess the safety and tolerability of combination treatment with relugolix, a phase 1 study in men with aPC has been undertaken. Methods: This is a three-part, open-label, parallel-cohort safety and tolerability study of relugolix in combination with abiraterone acetate in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) (Part 1), apalutamide in men with mCSPC or non-metastatic catration-resistant prostate cancer (nmCRPC) (Part 2), or docetaxel in men with mCSPC or mCRPC (Part 3). Each part of the study consists of a 45-day screening period, a 12-wk primary study treatment period and a 40-wk safety extension treatment period. All of the men are required to have been treated with leuprolide acetate or a GnRH receptor antagonist (eg, degarelix) in combination with abiraterone acetate for a minimum of 12 wks, apalutamide for a minimum of 6 wks, or docetaxel for a minimum of one treatment cycle prior to the baseline (Day 1) visit. Men will be transitioned from leuprolide acetate or degarelix to relugolix (120 mg [Part 1 and 3] or 240 mg [Part 2] once daily after a single loading dose of 360 mg); on the approximate date the next analog or antagonist injection is scheduled; treatment with each combination treatment will continue as previously prescribed. Hence, the study will provide safety and tolerability of relugolix and the three different combination agents for up to 1 year and in addition, will provide safety and tolerability data as men transition from injectable leuprolide acetate or degarelix to oral treatment with relugolix. Enrollment into the study began in March 2021. A protocol amendment was approved in July 2021 to include Part 2 and Part 3 of the study and to add the 40-wk safety extension treatment period. Screening for Part 2 was initiated in August 2021 and for Part 3 it is expected to initiate in January 2022. Clinical trial information: NCT04666129.

Cardiovascular Toxicities of Androgen Deprivation Therapy.

Opinion statementProstate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.

Bipotent Progenitors Do Not Require Androgen Receptor for Luminal Specification during Prostate Organogenesis.

SummaryAndrogen receptor (AR) plays a fundamental role in most aspects of adult prostate homeostasis, and anti-androgen therapy represents the cornerstone of prostate cancer treatment. However, early prostate organogenesis takes place during pre-pubertal stages when androgen levels are low, raising the possibility that AR function is more limited during prostate development. Here, we use inducible AR deletion and lineage tracing in genetically engineered mice to show that basal and luminal epithelial progenitors do not require cell-autonomous AR activity during prostate development. We also demonstrate the existence of a transient bipotent luminal progenitor that can generate luminal and basal progeny, yet is also independent of AR function. Furthermore, molecular analyses of AR-deleted luminal cells isolated from developing prostates indicate their similarity to wild-type cells. Our findings suggest that low androgen levels correlate with luminal plasticity in prostate development and may have implications for understanding how AR inhibition promotes lineage plasticity in prostate cancer.

Metabolic changes in patients with prostate cancer with androgen deprivation therapy

Prostate cancer is the most common type of cancer among men. Androgen deprivation therapy (ADT) is the most effective treatment for this disease. The cornerstone of prostate cancer treatment is the inhibition of testosterone production, which interrupts testosterone-induced growth of the prostate tumour. A sharp decrease in testosterone, however, has several undesirable effects on the metabolic profile and bone metabolism and can also lead to fatigue, loss of libido, gynecomastia and anaemia, provoke vasomotor hyperaemia and generally affect the quality of life. To increase the good (long-term) survival of patients with prostate cancer, studying the side effects associated with treatment is important, and therefore, in every clinical situation, the benefits of ADT must be compared with the side effects associated with the treatment. This article focuses on the described metabolic complications of ADT, including obesity, diabetes, lipid changes, metabolic syndrome and cardiovascular diseases. It also contains practical recommendations for managing the side effects and complications based on the available guidelines issued by the medical professional community.

Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses.

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Effect of Androgen Deprivation Therapy on Metabolic Complications and Cardiovascular Risk.

Androgen deprivation therapy (ADT) has been the cornerstone of prostate cancer treatment. ADT delays cancer progression, alleviates cancer-related symptoms, and is associated with survival gains. Despite these established benefits, the extended duration of therapy comes with known side effects. Furthermore, research from the past decade has generated increased awareness for more potentially lethal cardiometabolic consequences of ADT. In this review, we explore the relationship between ADT and cardiometabolic effects. Current literature on this complex relationship remains conflicting, due to a variety of factors, including study design (randomized vs. observational), treatment decision-making, and patient factors. Looking to the future, a combination of well-designed, randomized controlled trials and high-quality, real-world evidence are needed to definitely establish any ADT cardiovascular safety signal and to evaluate the efficacy of potential screening and therapeutic interventions. Furthermore, a collaborative, integrated approach among all health care professionals is critical to accurately delineate patients' potential risk/benefit treatment options.