OBJECTIVE: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC.
METHODS: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC.
RESULTS: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells.
CONCLUSIONS: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.

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 de novo 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. De novo 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 (INSM1) 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 (TP53) and retinoblastoma 1 (RB1). 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 TP53 and RB1 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.

UNASSIGNED: This study aimed to evaluate the relative efficacy and safety of first-line treatment options for metastatic castration-resistant prostate cancer (mCRPC).
UNASSIGNED: We systematically searched electronic databases, including PubMed and Web of Science, for studies published from their inception to April 3rd, 2023. Inclusion criteria were: 1) Completed Phase III or IV randomized controlled trials (RCTs) registered on ClinicalTrials.gov; 2) Patients with a confirmed diagnosis of mCRPC who had not previously received chemotherapy or novel endocrine therapies. We conducted a network meta-analysis using R software (version 3.4.0). Network graphs and risk of bias graphs were generated using Stata 14.0 and RevMan 5.4, respectively. The primary outcome was overall survival (OS), and the secondary outcome was the incidence of severe adverse events (SAEs).
UNASSIGNED: Seven RCTs encompassing 6,641 patients were included. The network meta-analysis revealed that both docetaxel+prednisone (DP) and cabazitaxel+prednisone (CP) significantly improved OS compared to abiraterone. Compared to placebo, DP showed comparable results to both cabazitaxel 20 mg/m^2+prednisone (C20P) and cabazitaxel 25 mg/m^2+prednisone (C25P) in terms of OS. For SAEs, both DP and C20P were superior to C25P, with no statistical difference between C20P and DP. The probability ranking plots indicated that C25P ranked highest for OS, while DP ranked highest for SAEs.
UNASSIGNED: Based on our network meta-analysis, we recommend cabazitaxel 20 mg/m^2+prednisone (C20P) as the primary choice for first-line management of mCRPC, followed by DP. Enzalutamide and abiraterone are suggested as subsequent options. Radium-223 may be considered for patients presenting with bone metastases.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42023443943.

Prostate cancer is a leading diagnosis and major cause of cancer-related deaths in men worldwide. As a typical hormone-responsive disease, prostate cancer is commonly managed with androgen deprivation therapy (ADT) to curb its progression and potential metastasis. Unfortunately, progression to castration-resistant prostate cancer (CRPC), a notably more aggressive phase of the disease, occurs within a timeframe of 2-3 years following ADT. Enzalutamide, a recognized androgen receptor (AR) antagonist, has been employed as a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC) since it was first approved in 2012, due to its ability to prolong survival. However, scientific evidence suggests that sustained treatment with AR antagonists may induce acquired AR mutations or splice variants, such as AR F877L, T878A, and H875Y, leading to drug resistance and thereby diminishing the therapeutic efficacy of these agents. Thus, the establishment of prostate cancer models incorporating these particular mutations is essential for developing new therapeutic strategies to overcome such resistance and evaluate the efficacy of next-generation AR-targeting drugs. We have developed a CRISPR (clustered regularly interspaced short palindromic repeats)-based knock-in technology to introduce an additional F877L mutation in AR into the human prostate cell line LNCaP. This article provides comprehensive descriptions of the methodologies for cellular gene editing and establishment of an in vivo model. Using these methods, we successfully identified an enzalutamide-resistant phenotype in both in vitro and in vivo models. We also assessed the efficacy of target protein degraders (TPDs), such as ARV-110 and ARV-667, in both models, and the corresponding validation data are also included here. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Generation of AR F877L-mutated LNCaP cell line using CRISPR technology Basic Protocol 2: Validation of drug resistance in AR F877L-mutated LNCaP cell line using the 2D CTG assay Support Protocol: Testing of sgRNA efficiency in HEK 293 cells Basic Protocol 3: Validation of drug resistance in AR F877L-mutated LNCaP cell line in vivo.

In 2024, there will be an estimated 1,466,718 cases of prostate cancer (PC) diagnosed globally, of which 299,010 cases are estimated to be from the US. The typical clinical approach for PC involves routine screening, diagnosis, and standard lines of treatment. However, not all patients respond to therapy and are subsequently diagnosed with treatment emergent neuroendocrine prostate cancer (NEPC). There are currently no approved treatments for this form of aggressive PC. In this review, a compilation of the clinical trials regimen to treat late-stage NEPC using novel targets and/or a combination approach is presented. The novel targets assessed include DLL3, EZH2, B7-H3, Aurora-kinase-A (AURKA), receptor tyrosine kinases, PD-L1, and PD-1. Among these, the trials administering drugs Alisertib or Cabozantinib, which target AURKA or receptor tyrosine kinases, respectively, appear to have promising results. The least effective trials appear to be ones that target the immune checkpoint pathways PD-1/PD-L1. Many promising clinical trials are currently in progress. Consequently, the landscape of successful treatment regimens for NEPC is extremely limited. These trial results and the literature on the topic emphasize the need for new preventative measures, diagnostics, disease specific biomarkers, and a thorough clinical understanding of NEPC.

UNASSIGNED: Early recognition of castration-resistant state is of significance for timely adjustment of treatment regimens and improvement of prognosis.
UNASSIGNED: This study aims to screen new aptamers CRda8 and CRda21 which recognize castration resistant prostate cancer (CRPC) cells with high affinity and specificity by SELEX technology.
UNASSIGNED: The enrichment of specific aptamer candidates was monitored by flow cytometric analysis. The affinity and specificity of aptamer candidates were evaluated by flow cytometry and immunofluorescence assay. MR imaging of CRda21-conjugated polyethylene glycol (PEG)-Fe3O4 nanoparticles to CRPC was further explored in vivo.
UNASSIGNED: Both aptamers showed high specificity to target cells with dissociation constants in the nanomolar range, and did not recognize other tested cells. The staining of clinical tissue sections with fluorescent dye labeled aptamers showed that sections from CRPC exhibited stronger fluorescence while sections from benign prostatic hyperplasia and androgen dependent prostate cancer did not exhibit notable fluorescence. In vivo MRI demonstrated that CRda21-conjugated PEG-Fe3O4 had good affinity to CRPC and produced strong T2WI signal intensity reduction distinguished from peritumoral tissue.
UNASSIGNED: The high affinity and specificity of CRda8 and CRda21 make the aptamer hold potential for early recognition of castration-resistant state and diagnosis of CRPC at the cellular level.

The effect of low-dose apalutamide in nonmetastatic castration-resistant prostate cancer is unknown. We report the observation of therapy being administered at 25% of the recommended dose in an 80-year-old patient. Despite treatment discontinuation during COVID lockdowns, he survived three years without evidence of metastasis. This case gently invites us to reflect on the possibility of low-dose apalutamide in the elderly.

Previous studies have demonstrated that adipocytes promote prostate cancer (PCa) cell progression, which facilitates the development of PCa into castration-resistant prostate cancer (CRPC); however, the underlying mechanisms are still not fully understood. Matrix metalloproteinases (MMPs) are a group of proteases responsible for the degradation of extracellular matrix (ECM) and the activation of latent factors. In our study, we detected that MMP11 expression was increased in PCa patients and that a high level of MMP11 was correlated with poor prognosis. Furthermore, siRNA knockdown of MMP11 in CRPC cells not only blocked the delipidation and dedifferentiation of mature adipocytes but also reduced the lipid uptake and utilization of CRPC cells in a cell co-culture model. The number of mitophagosomes and the expression level of Parkin were increased in MMP11-silenced CRPC cells. Moreover, we found that simultaneous downregulation of MMP14 and MMP11 expression may benefit patient survival. Indeed, MMP11/14 knockdown in CRPC cells significantly decreased lipid metabolism and cell invasion, at least partly through the mTOR/HIF1α/MMP2 signaling pathway. Importantly, MMP11/14 knockdown dramatically delayed tumor growth in a xenograft mouse model. Consistently, the decreased lipid metabolism, Ki67 and MMP2 expression, as well as the increased Parkin level were also confirmed in in vivo experiments, further demonstrating the mechanisms responsible for the tumor-promoting effects of MMP11/14. Collectively, our study elucidated the role of MMP11 and MMP14 in the bidirectional crosstalk between adipocytes and CRPC cells and provided the rationale of targeting MMP11/14 for the treatment of CRPC patients.

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-β signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.