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Aging Apr 2024Prostate cancer (PCa) is the second disease threatening men's health, and anti-androgen therapy (AAT) is a primary approach for treating this condition. Increasing...
OBJECTIVE
Prostate cancer (PCa) is the second disease threatening men's health, and anti-androgen therapy (AAT) is a primary approach for treating this condition. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in the development of PCa and the process of AAT resistance. The objective of this study is to utilize bioinformatics methods to excavate lncRNAs association with AAT resistance and investigate their biological functions.
METHODS
AAT resistance-related risk score model (ARR-RSM) was established by multivariate Cox analysis. Paired clinical tissue samples of 36 PCa patients and 42 blood samples from patients with PSA over 4 ng/ml were collected to verify the ARR-RSM. , RT-qPCR, CCK-8 and clone formation assays were displayed to verify the expression and function of AL354989.1 and AC007405.2.
RESULTS
Pearson correlation analysis identified 996 lncRNAs were associated with AAT resistance (ARR-LncRs). ARR-RSM was established using multivariate Cox regression analysis, and PCa patients were divided into high-risk and low-risk groups. High-risk patients showed increased expression of AL354989.1 and AC007405.2 had poorer prognoses. The high-risk score correlated with advanced T-stage and -stage. The AUC of ARR-RSM outperformed tPSA in diagnosing PCa. Silencing of AC007405.2 and AL354989.1 inhibited PCa cells proliferation and AAT resistance.
CONCLUSIONS
In this study, we have discovered the clinical significance of AC007405.2 and AL354989.1 in predicting the prognosis and diagnosing PCa patients. Furthermore, we have confirmed their correlation with various clinical features. These findings provide potential targets for PCa treatment and a novel diagnostic and predictive indicator for precise PCa diagnosis.
Topics: Aged; Humans; Male; Androgen Antagonists; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Prognosis; Prostatic Neoplasms; RNA, Long Noncoding
PubMed: 38643469
DOI: 10.18632/aging.205754 -
Optimizing outcomes in men with prostate cancer: the cardiovascular event lowering (CaELo) pathways.The Canadian Journal of Urology Apr 2024Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are...
INTRODUCTION
Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are associated with increased cardiovascular risk.
MATERIALS AND METHODS
An 11-member panel of urologic, medical, and radiation oncologists (along with a men's health specialist and an endocrinologist/preventive cardiologist) met to discuss current practices and challenges in the management of cardiovascular risk in prostate cancer patients who are taking androgen deprivation therapies (ADT) including LHRH analogues, alone and in combination with androgen-targeted therapies (ATTs).
RESULTS
The panel developed an assessment algorithm to categorize patients by risk and deploy a risk-adapted management strategy, in collaboration with other healthcare providers (the patient's healthcare "village"), with the goal of preventing as well as reducing cardiovascular events. The panel also developed a patient questionnaire for cardiovascular risk as well as a checklist to ensure that all aspects of cardiovascular disease risk reduction are completed and monitored.
CONCLUSIONS
Prostate cancer patients receiving ADT with or without ATT need to be more zealously assessed for prevention and aggressively managed to reduce cardiovascular events. This can and should include participation from the entire multidisciplinary healthcare team.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Cardiovascular Diseases
PubMed: 38642459
DOI: No ID Found -
Journal of Nanobiotechnology Apr 2024Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal...
Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal tissues. More importantly, the ADT can easily lead to resistance by involving the activation of NF-κB signaling pathway and high infiltration of M2 macrophages in tumor microenvironment (TME). Herein, we developed a biomimetic nanotherapeutic platform by deriving cell membrane nanovesicles from cancer cells and probiotics to yield the hybrid cellular nanovesicles (hNVs), loading flutamide (Flu) into the resulting hNVs, and finally modifying the hNVs@Flu with Epigallocatechin-3-gallate (EGCG). In this nanotherapeutic platform, the hNVs significantly improved the accumulation of hNVs@Flu-EGCG in tumor sites and reprogramed immunosuppressive M2 macrophages into antitumorigenic M1 macrophages, the Flu acted on androgen receptors and inhibited tumor proliferation, and the EGCG promoted apoptosis of prostate cancer cells by inhibiting the NF-κB pathway, thus synergistically stimulating the antitumor immunity and reducing the side effects and resistance of ADT. In a prostate cancer mouse model, the hNVs@Flu-EGCG significantly extended the lifespan of mice with tumors and led to an 81.78% reduction in tumor growth compared with the untreated group. Overall, the hNVs@Flu-EGCG are safe, modifiable, and effective, thus offering a promising platform for effective therapeutics of prostate cancer.
Topics: Humans; Male; Animals; Mice; NF-kappa B; Androgens; Androgen Antagonists; Prostatic Neoplasms; Immunotherapy; Tea; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38637848
DOI: 10.1186/s12951-024-02458-9 -
BMC Cancer Apr 2024Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive...
Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.
BACKGROUND
Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression.
METHODS
We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety.
DISCUSSION
Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).
Topics: Male; Humans; Aged; Creatine; Resistance Training; Quality of Life; Androgen Antagonists; Prostatic Neoplasms; Androgens; Muscle Strength; Body Composition; Neoplastic Processes; Double-Blind Method; Dietary Supplements; Muscles; Polyesters; Randomized Controlled Trials as Topic
PubMed: 38637770
DOI: 10.1186/s12885-024-12260-3 -
BMC Cancer Apr 2024Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and...
Detecting androgen receptor (AR), AR variant 7 (AR-V7), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA) gene expression in CTCs and plasma exosome-derived cfRNA in patients with metastatic castration-resistant prostate cancer (mCRPC) by integrating the VTX-1 CTC...
BACKGROUND
Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported.
METHODS
To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay.
RESULTS
AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA.
CONCLUSION
VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.
Topics: Humans; Male; Androgen Receptor Antagonists; Biomarkers, Tumor; Cell-Free Nucleic Acids; Exosomes; Neoplastic Cells, Circulating; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; RNA, Messenger
PubMed: 38627648
DOI: 10.1186/s12885-024-12139-3 -
Asian Journal of Andrology Jul 2024This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the... (Meta-Analysis)
Meta-Analysis
This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e ., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.
Topics: Male; Humans; Network Meta-Analysis; Docetaxel; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Prostatic Neoplasms; Phenylthiohydantoin; Androstenes; Nitriles; Androgen Antagonists; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Randomized Controlled Trials as Topic; Pyrazoles
PubMed: 38624195
DOI: 10.4103/aja20242 -
Chronobiology International May 2024Chronotype, an individual's preferred sleep-wake timing, is influenced by sex and age. Men sometimes report a later chronotype than women and older age is associated...
Chronotype, an individual's preferred sleep-wake timing, is influenced by sex and age. Men sometimes report a later chronotype than women and older age is associated with earlier chronotype. The sex-related changes in chronotype coincide with puberty and menopause. However, the effects of sex hormones on human chronotype remain unclear. To examine the impact of 3 months of gender-affirming hormone therapy (GAHT) on chronotype in transgender persons, this study used data from 93 participants from the prospective RESTED cohort, including 49 transmasculine (TM) participants starting testosterone and 44 transfeminine (TF) participants starting estrogens and antiandrogens. Midpoint of sleep and sleep duration were measured using the ultra-short Munich ChronoType Questionnaire (µMCTQ). After 3 months of GAHT, TM participants' midpoint of sleep increased by 24 minutes (95% CI: 3 to 45), whereas TF participants' midpoint of sleep decreased by 21 minutes (95% CI: -38 to -4). Total sleep duration did not change significantly in either group. This study provides the first prospective assessment of sex hormone use and chronotype in transgender persons, showing that GAHT can change chronotype in line with cisgender sex differences. These findings provide a basis for future studies on biological mechanisms and clinical consequences of chronotype changes.
Topics: Humans; Male; Transgender Persons; Female; Circadian Rhythm; Prospective Studies; Sleep; Adult; Gonadal Steroid Hormones; Surveys and Questionnaires; Young Adult; Testosterone; Middle Aged; Time Factors; Transsexualism; Chronotype
PubMed: 38616311
DOI: 10.1080/07420528.2024.2339989 -
The Journal of Steroid Biochemistry and... Jul 2024Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone...
Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs. Using a GHD model in mice treated with Tibolone, we conducted proteomic analysis and identified a reprogrammed response to Tibolone, a compound that stimulates estrogenic, progestogenic, and androgenic pathways. Through a comprehensive network pharmacological workflow, we identified a reprogrammed response to Tibolone, particularly within "Pathways of Neurodegeneration", as well as interconnected pathways including "cellular respiration", "carbon metabolism", and "cellular homeostasis". Analysis revealed 23 proteins whose Tibolone response depended on GHD and/or sex, implicating critical processes like oxidative phosphorylation and calcium signalling. Our findings suggest the therapeutic efficacy of HTs may depend on these variables, suggesting a need for greater precision medicine considerations whilst highlighting the need to uncover underlying mechanisms.
Topics: Animals; Norpregnenes; Female; Mice; Proteomics; Estrogen Receptor Modulators; Neurodegenerative Diseases; Mice, Inbred C57BL; Male; Ovariectomy; Gonadal Hormones; Brain
PubMed: 38614433
DOI: 10.1016/j.jsbmb.2024.106520 -
Cancer Treatment Reviews May 2024Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT)... (Review)
Review
First-line combination treatment with PARP and androgen receptor-signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States.
INTRODUCTION
Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)-signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations.
SUMMARY
Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Male; Antineoplastic Combined Chemotherapy Protocols; Androgen Receptor Antagonists; Nitriles; Piperazines; Phthalazines; Phenylthiohydantoin; United States; Receptors, Androgen; Benzamides; Piperidines; Indazoles; Signal Transduction; Recombinational DNA Repair
PubMed: 38613872
DOI: 10.1016/j.ctrv.2024.102726 -
Chinese Medical Journal Jun 2024Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with...
Prevalence and risk evaluation of cardiovascular disease in the newly diagnosed prostate cancer population in China: A nationwide, multi-center, population-based cross-sectional study.
BACKGROUND
Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China.
METHODS
Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher's exact test was used for comparison of categorical variables.
RESULTS
A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk.
CONCLUSIONS
PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.
Topics: Humans; Male; Prostatic Neoplasms; Cardiovascular Diseases; China; Cross-Sectional Studies; Aged; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Aged, 80 and over; Androgen Antagonists
PubMed: 38613214
DOI: 10.1097/CM9.0000000000003087