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Frontiers in Oncology 2024The treatment preferences of Chinese physicians who treat nonmetastatic castration-resistant prostate cancer (nmCRPC) and how they weigh the benefits and risks of nmCRPC...
INTRODUCTION
The treatment preferences of Chinese physicians who treat nonmetastatic castration-resistant prostate cancer (nmCRPC) and how they weigh the benefits and risks of nmCRPC treatment are still unknown. This study aimed to evaluate Chinese physicians' benefit-risk treatment preferences for nmCRPC and assist in setting nmCRPC treatment goals.
METHODS
A paper-based discrete choice experiment (DCE) survey was administered to 80 nmCRPC-treating physicians. DCE responses were analyzed to produce the preference weight and the relative importance score for each attribute level. The marginal rate of substitution (MRS) was used to quantify the amount of overall survival (OS) physicians were willing to trade for a reduction in treatment-related adverse events (AEs). We further conducted the exploratory analysis, stratifying physicians from 5 perspectives into different subgroups and examining the treatment preferences and OS trade-off in each subgroup.
RESULTS
In terms of efficacy attributes, physicians placed greater emphasis on OS than time to pain progression. With regard to safety attributes, serious fracture was perceived as the most important AE by physicians, followed by serious fall, cognitive problems, skin rash, and fatigue. In the exploratory analysis, we found generally that physicians with less clinical practice experience and those from more economically developed regions placed more emphasis on AEs and were willing to give up more of their patients' OS to reduce the risk of AEs.
CONCLUSION
Physicians from mainland China value the importance of minimizing treatment-related AEs when considering different treatment options for patients with nmCRPC, and they are willing to trade a substantial amount of OS to avoid AEs.
PubMed: 38835395
DOI: 10.3389/fonc.2024.1382678 -
Acta Pharmaceutica Sinica. B Jun 2024Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed...
Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO), named HMnE&M@H, was established to encapsulate and deliver enzalutamide and MK-8776. This HA-modified nanosystem managed targeted activation pH/glutathione responsiveness. HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.
PubMed: 38828153
DOI: 10.1016/j.apsb.2024.03.012 -
The Journal of Steroid Biochemistry and... May 2024Steroid hormone receptors are key mediators in the execution of hormone action through a combination of genomic and non-genomic action. Since their isolation and...
Steroid hormone receptors are key mediators in the execution of hormone action through a combination of genomic and non-genomic action. Since their isolation and characterisation in the early 20th Century much of our understanding of the biological actions of steroid hormones are underpinned by their activated receptor activity. Over the past two decades there has been an acceleration of more omics-based research which has resulted in a major uptick in our comprehension of genomic steroid action. However, it is well understood that steroid hormones can induce very rapid signalling events in tandem with their genomic actions wherein they exert their influence through alterations in gene expression. Thus the totality of genomic and non-genomic steroid action occurs in a simultaneous and reciprocal manner and a greater appreciation of whole cell action is required to fully evaluate steroid hormone activity in vivo. In this mini-review we outline the most recent developments in non-genomic steroid action and cytoplasmic steroid hormone receptor biology in endocrine-related cancers with a focus on the 3-keto steroid receptors, in particular the androgen receptor.
PubMed: 38823459
DOI: 10.1016/j.jsbmb.2024.106559 -
Pharmacological Research Jul 2024After the initial androgen deprivation therapy (ADT), part of the prostate cancer may continuously deteriorate into castration-resistant prostate cancer (CRPC). The... (Review)
Review
After the initial androgen deprivation therapy (ADT), part of the prostate cancer may continuously deteriorate into castration-resistant prostate cancer (CRPC). The majority of patients suffer from the localized illness at primary diagnosis that could rapidly assault other organs. This disease stage is referred as metastatic castration-resistant prostate cancer (mCRPC). Surgery and radiation are still the treatment of CRPC, but have some adverse effects such as urinary symptoms and sexual dysfunction. Hormonal castration therapy interfering androgen receptor (AR) signaling pathway is indispensable for most advanced prostate cancer patients, and the first- and second-generation of novel AR inhibitors could effectively cure hormone sensitive prostate cancer (HSPC). However, the resistance to these chemical agents is inevitable, so many of patients may experience relapses. The resistance to AR inhibitor mainly involves AR mutation, splice variant formation and amplification, which indicates the important role in CRPC. Proteolysis-targeting chimera (PROTAC), a potent technique to degrade targeted protein, has recently undergone extensive development as a biological tool and therapeutic drug. This technique has the potential to become the next generation of antitumor therapeutics as it could overcome the shortcomings of conventional small molecule inhibitors. In this review, we summarize the molecular mechanisms on PROTACs targeting AR signaling for CRPC, hoping to provide insights into drug development and clinical medication.
Topics: Humans; Prostatic Neoplasms, Castration-Resistant; Male; Receptors, Androgen; Signal Transduction; Animals; Proteolysis; Androgen Receptor Antagonists; Antineoplastic Agents; Proteolysis Targeting Chimera
PubMed: 38815882
DOI: 10.1016/j.phrs.2024.107234 -
Scientific Reports May 2024Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate...
Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate classification for the "Fudan University Shanghai Cancer Center (FUSCC) subtyping" has been developed and is considered more suitable for clinical application. Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing and the specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. AKT1 and BRCA1 mutations were identified as independent prognostic factors in TNBC. TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of TNBC stratified therapy in the future.
Topics: Humans; Triple Negative Breast Neoplasms; Female; Mutation; Middle Aged; Proto-Oncogene Proteins c-akt; Prognosis; Class I Phosphatidylinositol 3-Kinases; Genomics; BRCA1 Protein; Adult; Biomarkers, Tumor; Aged; High-Throughput Nucleotide Sequencing; B7-H1 Antigen
PubMed: 38811720
DOI: 10.1038/s41598-024-62991-3 -
World Journal of Clinical Cases May 2024Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can...
Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer. NEPC may arise or develop following androgen deprivation therapy (ADT). NEPC that arise following ADT has the nomenclature "treatment-emerging/induced NEPC (t-NEPC)". t-NEPC would be anticipated in castration resistant prostate cancer (CRPC) and metastatic PCa. t-NEPC is characterized by low or absent androgen receptor (AR) expression, independence of AR signaling, and gain of neuroendocrine phenotype. t-NEPC is an aggressive metastatic tumor, develops from PCa in response to drug induced ADT, and shows very short response to conventional therapy. t-NEPC occurs in 10%-17% of patients with CRPC. NEPC is rare and is accounting for less than 2% of all PCa. The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated. Sphingosine kinase 1 plays a significant role in t-NEPC development. Although neuroendocrine markers: Synaptophysin, chromogranin A, and insulinoma associated protein 1 () are expressed in t-NEPC, they are non-specific for diagnosis, prognosis, and follow-up of therapy. t-NEPC shows enriched genomic alteration in tumor protein P53 () and retinoblastoma 1 (). There are evidences suggest that t-NEPC might develop through epigenetic evolution. There are genomic, epigenetic, and transcriptional alterations that are reported to be involved in development of t-NEPC. Knock-outs of and were found to contribute in development of t-NEPC. PCa is resistant to immunotherapy, and at present there are running trials to approach immunotherapy for PCa, CRPC, and t-NEPC.
PubMed: 38808339
DOI: 10.12998/wjcc.v12.i13.2143 -
Frontiers in Physiology 2024In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are...
In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are necessary for maintaining normal physiological function for extended time periods. For men, who comprise nearly 80% of new SCI cases each year, testosterone is the most abundant circulating sex steroid. SCI often results in significantly reduced testosterone production and may result in chronic low testosterone levels. Testosterone plays a role in respiratory function and the expression of respiratory neuroplasticity. When testosterone levels are low, young adult male rats are unable to express phrenic long-term facilitation (pLTF), an inducible form of respiratory neuroplasticity invoked by acute, intermittent hypoxia (AIH). However, testosterone replacement can restore this respiratory neuroplasticity. Complicating the interpretation of this finding is that testosterone may exert its influence in three possible ways: 1) directly through androgen receptor (AR) activation, 2) through conversion to dihydrotestosterone (DHT) by way of the enzyme 5α-reductase, or 3) through conversion to 17β-estradiol (E2) by way of the enzyme aromatase. DHT signals via AR activation similar to testosterone, but with higher affinity, while E2 activates local estrogen receptors. Evidence to date supports the idea that exogenous testosterone supplementation exerts its influence through estrogen receptor signaling under conditions of low circulating testosterone. Here we explored both recovery of breathing function (measured with whole body barometric plethysmography) and the expression of AIH-induced pLTF in male rats following C2-hemisection SCI. One week post injury, rats were supplemented with either E2 or DHT for 7 days. We hypothesized that E2 would enhance ventilation and reveal pLTF following AIH in SCI rats. To our surprise, though E2 did beneficially impact overall breathing recovery following C2-hemisection, both E2 supplementation and DHT restored the expression of AIH-induced pLTF 2 weeks post-SCI.
PubMed: 38803364
DOI: 10.3389/fphys.2024.1390777 -
Frontiers in Genetics 2024The increasing incidence and mortality of prostate cancer worldwide significantly impact the life span of male patients, emphasizing the urgency of understanding its... (Review)
Review
The increasing incidence and mortality of prostate cancer worldwide significantly impact the life span of male patients, emphasizing the urgency of understanding its pathogenic mechanism and associated molecular changes that regulate tumor progression for effective prevention and treatment. RNA modification, an important post-transcriptional regulatory process, profoundly influences tumor cell growth and metabolism, shaping cell fate. Over 170 RNA modification methods are known, with prominent research focusing on N6-methyladenosine, N7-methylguanosine, N1-methyladenosine, 5-methylcytidine, pseudouridine, and N4-acetylcytidine modifications. These alterations intricately regulate coding and non-coding RNA post-transcriptionally, affecting the stability of RNA and protein expression levels. This article delves into the latest advancements and challenges associated with various RNA modifications in prostate cancer tumor cells, tumor microenvironment, and core signaling molecule androgen receptors. It aims to provide new research targets and avenues for molecular diagnosis, treatment strategies, and improvement of the prognosis in prostate cancer.
PubMed: 38798700
DOI: 10.3389/fgene.2024.1380746 -
BioRxiv : the Preprint Server For... May 2024There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects...
There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.
PubMed: 38798471
DOI: 10.1101/2024.05.08.593181 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward...
Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward elevated glycolysis is a hallmark of mCRPC. Our goal is to identify therapeutics specifically associated with high glycolysis. Here, we established a computational framework to identify new pharmacological agents for mCRPC with heightened glycolysis activity under a tumor microenvironment, followed by in vitro validation. First, using our established computational tool, OncoPredict, we imputed the likelihood of drug responses to approximately 1900 agents in each mCRPC tumor from two large clinical patient cohorts. We selected drugs with predicted sensitivity highly correlated with glycolysis scores. In total, 77 drugs predicted to be more sensitive in high glycolysis mCRPC tumors were identified. These drugs represent diverse mechanisms of action. Three of the candidates, ivermectin, CNF2024, and P276-00, were selected for subsequent vitro validation based on the highest measured drug responses associated with glycolysis/OXPHOS in pan-cancer cell lines. By decreasing the input glucose level in culture media to mimic the mCRPC tumor microenvironments, we induced a high-glycolysis condition in PC3 cells and validated the projected higher sensitivity of all three drugs under this condition ( < 0.0001 for all drugs). For biomarker discovery, ivermectin and P276-00 were predicted to be more sensitive to mCRPC tumors with low androgen receptor activities and high glycolysis activities (AR(low)Gly(high)). In addition, we integrated a protein-protein interaction network and topological methods to identify biomarkers for these drug candidates. and were identified as key biomarkers for ivermectin and CNF2024, respectively, through multiple independent biomarker nomination pipelines. In conclusion, this study offers new efficacious therapeutics beyond traditional androgen-deprivation therapies by precisely targeting mCRPC with high glycolysis.
PubMed: 38794139
DOI: 10.3390/ph17050569