Prostate Cancer, Castration-Resistant Prostate Cancer (CRPC), Radium-223 Dichloride Injection for Bone Metastasized Prostate Cancer

Purpose: The purpose of this paper is to discuss the most important facts about prostate cancer, its treatments and efficacy, the type of prostate cancer that does not improve with hormonal therapy (Castration-Resistant Prostate Cancer-CRPC), and the recently approved Radium-223 dichloride targeted therapy for CRPC that has metastasized to bones. Prostate cancer is the third most common malignancy diagnosed worldwide and the most common malignant disease in men. Also, the incidence of prostate cancer varies between regions. So it’s important to have a proper understanding of all above points to prevent the further development and spread of cancer and improve the cure rate. Design: The paper begins by discussing what prostate cancer is, the risk factors, clinical manifestations, and the treatments for prostate cancer. It covers the clinical manifestations, pathology, screening (cancer biomarker Prostate Specific Antigen, Digital Rectal Examination—DRE, prostate biopsy, and imaging) and treatments for prostate cancer. The paper then delves into the main treatment methods for prostate cancer, including how Castration-Resistant Prostate Cancer (CRPC) differs from normal prostate cancer after hormone suppression therapy. Additionally, it discusses the effectiveness of the recently introduced Radium-223 dichloride injection as a radiation-targeted therapy for treating CRPC that has metastasized to bones. This section covers the properties of radium-223 dichloride injection, its pharmacokinetics, pharmacodynamics, absorption and volume of distribution, half-life, metabolism, route of elimination, clearance, toxicity, adverse effects, and mechanism of action at the tumor site. It also discusses preclinical studies related to radium-223 dichloride injection and its effectiveness in treating CRPC patients with bone metastasis. Conclusion: Prostate cancer is a common cancer that can be treated with surgery or hormonal therapy. However, if the cancer progresses despite hormonal therapy, Radium-223 dichloride injection can be used as a radiation target therapy to treat patients with CRPC and symptomatic bone metastases. This treatment kills tumor cells in bones and reduces associated pain with minimal damage to surrounding normal tissue. However, the metastatic disease cannot be cured and can only offer palliation for the patient. Suggestions: Based on the facts, Radium-223 target therapy is effective in treating and providing palliation for cancers. It is suggested to further develop the usage of radiation target therapy and to test the safety and efficacy of more than 6 injections of Radium-223 dichloride and its combination with currently used chemotherapy drugs for bone metastasized CRPC. This paper aims to contribute to future research designs related to cancer therapies using radiation and to design new studies and practical implementations, especially regarding the usage of radium-223 dichloride.

Comprehensive treatment for metastatic castration-resistant prostate cancer with neuroendocrine differentiation:a case report

Retrospective analysis of the progression of a case of metastatic castration-resistant prostate cancer with neuroendocrine differentiation:the patient was a 65 year old man with prostate adenocarcinoma on prostate biopsy,Gleason 4+4 score=8,70%,ISUP4 group,localized invasion of nerves.Progressed to metastatic castration-resistant prostate cancer after 8 months of novel endocrine therapy,persistent elevated PSA after endocrine therapy,chemotherapy,and radiation,abdominal metastasis,brain metastasis,gastric metastasis,and staging as neuroendocrine differentiation after second prostate biopsy,which is a highly malignant subtype and has been concerned as a mechanism of resistance to targeted therapies.We discuss how to choose a more optimal treatment plan and outline the patient's diagnostic and therapeutic course.We provide a reflection for the clinical study of metastatic castration-resistant prostate cancer with neuroendocrine type.

Prognostic factors in Chinese patients with metastatic castration-resistant prostate cancer treated with docetaxel-based chemotherapy

This study aims to evaluate the potential value of patient characteristics in predicting overall survival （OS） in patients with metastatic castration-resistant prostate cancer （mCRPC） treated with docetaxel-based thermotherapy. A total of 115 patients with mCRPC undergoing a docetaxel q3w regimen were enrolled in this study. A survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the prognostic value of all covariates for OS. OS was also analysed after stratifying patients according to the results of multivariate analysis. The median OS for the entire cohort was 17.0 months. The multivariate analysis showed that the prostate-specific antigen doubling time （PSADT）, baseline haemoglobin （Hb） concentration, alkaline phosphatase （ALP） concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS. According to the presence of PSADT 〈46.3 days and baseline ALP/〉 110 IU 1-1, all patients were divided into three risk groups： low-risk group （no risk factors）, intermediate-risk group （one risk factor） and high-risk group （two risk factors）. Median OSs for patients in low-, intermediate- and high-risk groups were 28.0 months （95% Ch 23.8-32.2）, 21.0 months （95% Ch 18.9-23.1） and 11.0 months （95% Ch 7.6-14.4）, respectively （P〈O.O01）. In conclusion, PSADT, baseline Hb concentration, ALP concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS in Chinese patients with mCRPC treated with docetaxel. PSADT combined with the baseline ALP concentration could be a useful risk stratification parameter for evaluating survival outcomes.

Surface-enhanced Raman spectroscopy of serum predicts sensitivity to docetaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

Docetaxel-based chemotherapy,as the first-line treatment for metastatic castration-resistant prostate cancer(mCRPC),has succeeded in helping quite a number of patients to improve quality of life and prolong survival time.However,almost half of mCRPC patients are not sensitive to docetaxel chemotherapy initially.This study aimed to establish models to predict sensitivity to docetaxel chemotherapy in patients with mCRPC by using serum surface-enhanced Raman spectroscopy(SERS).A total of 32 mCPRC patients who underwent docetaxel chemo-therapy at our center from July 2016 to March 2018 were included in this study.Patients were dichotomized in prostate-specific antigen(PSA)response group(n=17)versus PSA failure group(n=15)according to the response to docetaxel.In total 64 matched spectra from 32 mCRPC patients were obtained by using SERS of serum at baseline(q0)and after 1 cycle of docetaxel chemotherapy(ql).Comparing Raman peaks of serum samples at baseline(q0)be-tween two groups,significant differences revealed at the peaks of 638,810,890(p<0.05)and 1136cm^(-1)(p<0.01).The prediction models of peak 1363 cm^(-1)and principal component anal-ysis and linear discriminant analysis(PCA-LDA)based on Raman data were established,re-spectively.The sensitivity and specificity of the prediction models were 71%,80%and 69%,78%through the way of leave-one-out cross-validation.According to the results of five-cross-valida-tion,the PCA-LDA model revealed an accuracy of 0.73 and AUC of 0.83.

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（^-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （OS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.

Comparative analysis of the effectiveness of abiraterone before and after docetaxel in patients with metastatic castration-resistant prostate cancer

AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.

The effectiveness of the TAX 327 nomogram in predicting overall survival in Chinese patients with metastatic castration-resistant prostate cancer

Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer （mCRPC） after first-line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first-line chemotherapy （docetaxel or mitoxantrone） were identified. Because clinical trials are limited in China's Mainland, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months （docetaxel） and 19 months （mitoxantrone） at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 （95% CI： 0.54-0.70）. The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary.

The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer： who can benefit from ketoconazole therapy？

We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer （mCRPC）. In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone. Progression-free survival （PFS） was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months （0.5-8.6 months） for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen （PSA） declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following： 1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and 〈0.2 ng ml- 1, respectively （hazard rate （HR）=4.767, P〈0.001）; 3.1 and 1.6 months for a baseline testosterone of ≥0.1 and 〈0.1 ng m1-1, respectively （HR=2.865, P=0.012）; 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and 〈120 g 1-1, respectively （HR= 1.605, P〈0.001）; and 3.0 and 1.9 months for a PSA doubling time （PSADT） of ≥ 2.0 and 〈2.0 months, respectively （HR= 1.454, P=-0.017）. A risk model was constructed according to the four factors that divided patients into three subgroups of low risk （0-1 factors）, moderate risk （2 factors） and high risk （3-4 factors） with PFS values of 3.6, 3.0 and 1.4 months, respectively （HR=1.619, P〈0.001）. A nadir PSA of ≥0.2 ng m1-1, a baseline testosterone of 〈0.1 ng m1-1, a baseline haemoglobin of 〈 120 g I- 1 and a PSADT of 〈2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.

Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease

Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.

Practice patterns and outcomes of equivocal bone scans for patients with castration-resistant prostate cancer: Results from SEARCH

Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.Methods:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal scans.Men with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan report.All follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were reviewed.Variables were compared between patients with a positive vs.negative follow-up imaging after an equivocal bone scan.Results:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were positive.Among those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with high-risk.These preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.

Androgen receptor mediated resistance in the progression of castration-resistant prostate cancer

The incidence of prostate cancer has increased year by year in the world.Despite improvements in diagnosis,surgical techniques,and drugs,survival rates of prostate cancer have improved little,and most prostate cancer-related deaths are as a result of castration resistant prostate cancer(CRPC),which progresses and metastasizes after surgical or medical castration.The pathogenesis of CRPC is still unclear.It has been found that the majority of CRPC patients have overexpression of androgen receptors(ARs),and there are many forms of changes in the signaling pathways that intersect with them during he process to CRPC.Micro ribonucleic acid(miRNA)plays an important role in regulating the expression and translation of prostate cancer target genes,and in the life cycle of cell cycle distribution and apoptosis.Relatedly,active changes in miRNA expression are also closely related to androgen.Therefore,the study of AR-related signaling pathways and AR and miRNA-related signaling pathways is of great significance in the treatment of CRPC.

End points of clinical trials in metastatic castration-resistant prostate cancer:A systematic review

AIM： To review the defnition and performance of the commonly used end points in trials of systemic thera-pies in metastatic castration-resistant prostate cancer patients. METHODS： A literature search was undertaken on PubMed database to identify studies meeting estab-lished criteria, with the aim of selecting randomized clinical trials and study definition and performance of their end points. The end points were grouped into three categories： overall survival （OS）, time-to-event end points, and response end points. A special analysis was performed for secondary end points of the studies which documented a beneft in OS in the experimental arm. Finally, publishes analyses for surrogacy of the in-cluded end points were also reported. RESULTS： OS, time-to-event and response end points in 31 selected trials were analyzed. OS was the pri-mary end point in 14 trials, and the secondary end point in 17. A time-to-event end point was the primaryend point in 8 studies, and the secondary end point in 22; the most reported time-to-event end points were composite end points, and the events changed among trials. A response end point was the primary end point in 9 studies, in 3 it was prostate-specifc antigen （PSA）-related, in 3 pain-related and in 3 mixed. A response end point was the secondary end point in 19 studies： PSA response and radiologic response were the most frequently used secondary end points in 19 and 11 tri-als, respectively, while pain response was used in 5 studies.CONCLUSION： A homogeneous defnition of progres-sion in future trials is mandatory. Among response end points, pain-response and PSA-response appear to be the most reliable.

Radiotherapy of Oligoprogressive Lesions in Castration-Resistant Prostate Cancer: Impact on Second-Generation Hormone Therapy

Background: The therapeutic standard for oligoprogressive prostate cancer resistant to castration is second-generation hormone therapy. This systemic treatment is expensive. There are oligoprogressive lesions accessible to radiotherapy. Objectives: To study the impact of radiotherapy of oligoprogressive lesions on the implementation of second generation hormone therapy. Patients and Methods: A retrospective study from 2012 to 2020 was carried out. All patients with oligoprogressive prostate cancer who had received radiotherapy on one or more lesions in progression were collated. Survival was calculated using the Kaplan-Meier method. Results: 8 patients were treated with stereotactic and conformational radiotherapy between August 2012 and August 2020 in the context of oligoprogressive prostate cancer resistant to castration. The median age at diagnosis of oligoprogression was 73 years with a median PSA level of 3.11 ng/ml. Nine lesions were diagnosed with PET scan PSMA. All the lesions were treated by radiotherapy with different regimens. After a median follow-up of 12.5 months, 7 patients showed a biochemical response to treatment with a median decrease in PSA of 67%. The median survival without clinical or biochemical progression was 7 months. The median survival without the need for further systemic treatment was 9 months. During the follow-up period, six patients received second-generation hormone therapy to treat their relapse, and the other two showed no clinical or biochemical relapse. Conclusion: Radiotherapy may be an alternative to delay the introduction of difficult-to-access second-generation hormone therapy in developing countries. A prospective study could validate this therapeutic approach.

PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

IL-6/IL-6R as a potential key signaling pathway in prostate cancer development

Interleukin-6(IL-6)is a pleiotropic cytokine involved in prostate regulation and in prostate cancer(PC)development/progression.IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells.The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression.Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients.In PC treatment,patients diagnosed with advanced stages are frequently submitted to hormonal castration,although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer(CRPC).Therefore,it is important to understand the mechanisms involved in CRPC.Several pathways have been proposed to be involved in CRPC development,and their understanding will improve the way to more effective therapies.In fact,the prostate is known to be dependent,not exclusively,on androgens,but also on growth factors and cytokines.The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression,under androgen deprivation conditions.The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway.Furthermore,we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions.The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.

The role of mRNA splicing in prostate cancer

Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.

A rare case of isolated castrate resistant bilateral testicular metastases in advanced prostate cancer

Testicular metastasis is rare with the prostate being the most common site of primary cancer.We report a case of a 72-year-old man with castration-resistant prostate cancer(CRPC)and known metastases to bone and lymph nodes,who developed bilateral painful swollen testes 3 years after the initial diagnosis of prostate cancer.He had first presented with lower urinary tract symptoms(LUTS)with suspicious findings on digital rectal examination of the prostate,and an elevated serum prostate specific antigen(PSA)level of 129 ng/mL.Transrectal prostate biopsy revealed Gleason 4þ5 adenocarcinoma.Radiological staging showed locally advanced prostate cancer with extensive metastases to bone and pelvic and retroperitoneal lymph nodes.He was given hormonal therapy for over 2 years until progression to CRPC.Six months later he developed painful bilateral testicular swellings,and serum markers for testicular germ cell cancer were normal.Bilateral orchiectomy was performed,showing metastatic prostate cancer(Gleason 4þ5)on histology.One month postoperatively his PSA level dropped to 0.1 ng/mL from a presurgery level of 6.24 ng/mL.

Loss of NEIL3 activates radiotherapy resistance in the progression of prostate cancer

Objective:To explore the genetic changes in the progression of castration-resistant prostate cancer(CRPC)and neuroendocrine prostate cancer(NEPC)and the reason why these cancers resist existing therapies.Methods:We employed our CRPC cell line microarray and other CRPC or NEPC datasets to screen the target gene NEIL3.Lentiviral transfection and RNA interference were used to construct overexpression and knockdown cell lines.Cell and animal models of radiotherapy were established by using a medical electron linear accelerator.Flow cytometry was used to detect apoptosis or cell cycle progression.Western blot and qPCR were used to detect changes in the protein and RNA levels.Results:TCGA and clinical patient datasets indicated that NEIL3 was downregulated in CRPC and NEPC cell lines,and NEIL3 was correlated with a high Gleason score but a good prognosis.Further functional studies demonstrated that NEIL3 had no effect on the proliferation and migration of PCa cells.However,cell and animal radiotherapy models revealed that NEIL3 could facilitate the radiotherapy sensitivity of PCa cells,while loss of NEIL3 activated radiotherapy resistance.Mechanistically,we found that NEIL3 negatively regulated the expression of ATR,and higher NEIL3 expression repressed the ATR/CHK1 pathway,thus regulating the cell cycle.Conclusions:We demonstrated that NEIL3 may serve as a diagnostic or therapeutic target for therapy-resistant patients.

Radium-223 in metastatic castration resistant prostate cancer

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer （mCRPC）. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleuceI-T, cabazitaxel, abiraterone, enzalutamide and （most recently） radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer （e.g. samarium-153 and strontium-89）, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

Therapeutic targeting of the androgen receptor(AR)and AR variants in prostate cancer

Prostate cancer(PCa)accounted for over 300000 deaths world-wide in 2018.Most of the PCa deaths occurred due to the aggressive castration-resistant PCa(CRPC).Since the androgen receptor(AR)and its ligands contribute to the continued growth of androgendependent PCa(ADPCa)and CRPC,AR has become a well-characterized and pivotal therapeutic-target.Although AR signaling was identified as therapeutic-target in PCa over five-decades ago,there remains several practical issues such as lack of antagonist-bound AR crystal structure,stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction,unfavorable large-molecule accommodation of the ligand-binding domain(LBD),and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs.This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future ARtargeted drug development of potent next-generation molecules.The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.