Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

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“treatmentemerging/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.

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.

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.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

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.

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.

Future Directions in Metastatic Castration Resistant Prostate Cancer (mCRPC): Clinical Rationale and Use of New-Generation Hormonal Therapies

Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.

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.

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics

This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

醋酸阿比特龙联合泼尼松对mCRPC患者尿流动力学指标及PNI、NLR水平的影响

目的观察醋酸阿比特龙联合泼尼松对转移性去势抵抗性前列腺癌(mCRPC)患者尿流动力学指标及预后营养指数(PNI)、中性粒细胞/淋巴细胞比(NLR)水平的影响。方法前瞻性选取2020年1月至2022年12月达州市中西医结合医院收治的84例mCRPC患者为对象,按照随机数字表法将其分为观察组与对照组,每组各42例。对照组给予泼尼松治疗,观察组给予醋酸阿比特龙联合泼尼松治疗。比较两组临床疗效,检测并比较两组治疗4周后的尿流动力学指标[最大尿流率(MFR)、剩余尿量(RVP)]、前列腺特异性抗原(PSA)、睾酮、嗜铬粒蛋白A(CgA)、PNI值、NLR值的水平,并比较两组的不良反应发生情况。结果观察组的总有效率为85.71%,高于对照组(66.67%),差异有统计学意义(P<0.05)。治疗4周后,观察组MFR为(13.98±1.56)mL/s,高于对照组[(12.28±1.44)mL/s],RVP为(21.11±2.23)mL,低于对照组[(25.23±2.17)mL],差异均有统计学意义(P<0.05)。治疗4周后,观察组总前列腺特异性抗原(tPSA)、游离前列腺特异性抗原(fPSA)、睾酮、CgA水平分别为(18.54±10.74)、(7.78±2.05)、(0.63±0.10)、(96.85±15.65)ng/mL,均低于对照组[(32.56±12.02)、(13.23±4.11)、(0.81±0.12)、(105.63±21.14)ng/mL],差异均有统计学意义(P<0.05)。治疗4周后,观察组PNI值为56.58±10.11,高于对照组(51.29±9.74),NLR值为2.09±0.19,低于对照组(2.43±0.21),差异均有统计学意义(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论醋酸阿比特龙联合泼尼松可调节mCRPC患者PSA、睾酮及PNI、NLR的水平,改善尿流动力学,提高疗效。

Intensity of stromal changes is associated with tumor relapse in clinically advanced prostate cancer after castration therapy

Reactive stromal changes in prostate cancer （PCa） are likely involved in the emergence of castration-resistant PCa （CRPC）. This study was designed to investigate stromal changes in patients with clinically advanced PCa and analyze their prognostic significance. Prostate needle biopsies obtained from 148 patients before castration therapy were analyzed by Masson trichrome staining and immunohistochemical analysis of vimentin and desmin. Reactive stroma grading was inversely correlated with Gleason score. Stroma grade （Masson stain 82.8% vs 45.6%, P 〈 0.001） and vimentin expression （P = 0.005） were significantly higher, and desmin expression （P = 0.004） significantly lower, in reactive stroma of tumors with a Gleason score of 6-7 than in adjacent peritumoral tissue. Kaplan-Meier analysis showed a significant association between reactive stroma grade in tumors and the occurrence of CRPC in patients with a Gleason score of 6-7 （P= 0.009）. Furthermore, patients with higher vimentin or lower desmin expression had a shorter disease-free period. In multivariate analysis, only vimentin expression was a significant predictor of tumor relapse （hazard ratio 1.78, 95% confidence interval 1.12-10.26, P = 0.012）. These findings indicate that the intensity of reactive stroma is associated with castration responsiveness, especially in patients with a lower Gleason score where the abundant stroma component is most frequently found. High expression of vimentin in tumor stroma was independently associated with poor outcomes in patients with Gleason scores of 6-7, and may serve as a new prognostic marker in daily practice.

Role of androgen receptor splice variants in prostate cancer metastasis

Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(ADT)for treatment of patients with advanced PCa,most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer(mCRPC).Constitutively transcriptional activated AR splice variants(AR-Vs)have emerged as critical players in the development and progression of mCRPC.Among AR-Vs identified to date,AR-V7(a.k.a.AR3)is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues.Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival,growth,differentiation and migration in prostate cells.In this review,we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.

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.

去势抵抗性前列腺癌(CRPC)的形成机制及其免疫治疗研究进展

前列腺癌(prostate cancer,PCa)是困扰全球男性的恶性生殖系统疾病,疾病起始阶段对雄激素剥夺疗法(ADT)表现出良好应答。然而,患者不可避免地出现激素抵抗,从而进展为去势抵抗性前列腺癌(CRPC),极大降低患者生存率。临床上对CRPC研究主要围绕雄激素受体(AR)展开,此外也存在AR旁路途径。本综述将围绕雄激素受体依赖与旁路两种途径,讨论CRPC的形成机制,以及针对CRPC患者的免疫治疗方案的研究进展。

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.

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.

IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation

Objective:Androgen deprivation therapy(ADT)is still the principal treatment option for prostate cancer(PCa).In addition to reactivation of androgen receptor signaling,the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa(CRPC).A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1,leading to apoptosis.Compared with IL-13Rα2,IL13Rα1 is more constitutively expressed in PCa cells,but its function in PCa remains to be established.Methods:We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting,flow cytometry,and cell proliferation assays.Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1,to elucidate its function.Results:In this study,we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients.IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions(P<0.01).Mechanistically,IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2(HK2),resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis.Furthermore,our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2.Notably,IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor,2-deoxy-D-glucose(P<0.01).Conclusions:Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis.IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.

Sequential maximum androgen blockade(MAB) in minimally symptomatic prostate cancer progressing after initial MAB: two case reports

＂Ihe management of castrate-resistant prostate cancer progressing after maximum androgen blockade （MAB） has evolved in the last decade with the development of several novel therapeutic options. However, the initial therapeutic strategy in these patients usually involves withdrawal of anti-androgen that can be associated with biochemical response in approximately 20% of patients. Notably; we have observed evidence of sustained biochemical response in two patients following second- and third-line MAB using rechallenge schedule of previously administered anti-androgen after latent interval. The possibility of response following sequential MAB using the same anti-androgen agent has not yet been reported.

Radium-223 and metastatic castration-resistant prostate cancer: All that glitters is not gold

After being approved by the National Drug Agency in several countries, Radium-223 (Ra-223) is gaining wide acceptance in the treatment of bone metastatic castration resistant prostate cancer. The exact mechanism of action remain unclear: The established model of direct alpha-particle irradiation from the remodelling bone surface, where Ra-223 accumulates, surrounding the tumor foci can explain a lethal effect only on metastatic microdeposits, but not on higher tumor burden. According to the &#x0201c;pre-metastatic niche model&#x0201d;, it is likely that Ra-223 targets several non-tumoral cell types of the tumor microenvironment involved in the complex mechanism of cancer bone homing and colonization. A deeper insight into this hypothetical mechanism will lead to a more accurate dosimetric approach and to find optimal sequencing and/or combination with the other therapeutic options.