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.

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.

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.

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.

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.

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.

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.

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.

The role of glutamine metabolism in castration-resistant prostate cancer

Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes.Among the many nutrients,glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa.In addition to amino acid metabolism,glutamine is also widely involved in the synthesis of other macromolecules and biomasses.Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients.This review summarizes the metabolic landscape of PCa,with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa,and suggests novel therapeutic strategies.

Overexpression of ETS-1 is associated with malignan＇ biological features of prostate cancer

E26 transformation-specific-1 （ETS-1）, an ETS family transcription factor, has been reported to play an important role in a variety of physiological and pathological processes, but clinical implications of ETS-1 expression in prostate cancer （PCa）, particularly high-risk cases, including response to androgen-deprivation therapy （ADT） have yet to be elucidated. We examined the expression of ETS- 1 using immunohistochemical staining of paraffin-embedded prostate carcinoma tissue obtained by needle biopsy from 69 mostly advanced PCa patients. ETS-1 expression was compared with the clinicopathological characteristics of the 69 patients, including 25 who underwent ADT as a primary treatment. As a result, PCa patients with higher expression of ETS-1 were significantly more likely to be of high stage and high Gleason score （P〈O.05）. There was no significant association between ETS-1 expression and the initial prostate-specific antigen （PSA） level. In the 25 patients treated by ADT, the staining score for ETS-1 was significantly associated with rapid development of castration-resistant disease within 24 months （P〈O.05）, whereas the Gleason score and PSA level were not. In conclusion, increased ETS-1 expression was associated with a higher stage, higher Gleason score and shorter time to castration-resistant progression. These data suggest that immunostaining for ETS-1 could be a molecular marker for predicting a poor clinical outcome for PCa patients, oarticularlv those with hi^h-risk disease.

Mismatch repair enzyme expression in primary and castrate resistant prostate cancer

Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients.MMR(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression arrays.Associations between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were determined.Results:There was no correlation between levels of MMR protein and BCR.Absence of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,respectively.MSH2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC respectively.Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death.However absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression level.This finding correlated with microsatellite instability previously reported in this CRPC cohort.

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.

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.

The Use of PSA Doubling Time to Predict Prognosis and the Use of PSA Response to Assess the Success for Prostate Cancer Patients Undergoing Docetaxel Chemotherapy

In the targeted therapy era, it is critical to know the certain points to start or discontinue chemotherapy for patients with castration resistant metastatic prostate cancer. The prognostic factors to determine this response are still not clear yet. We tried to find out if the PSA doubling time helps us to predict the patients who will benefit from docetaxel chemotherapy most, and also to question the value of the PSA response to chemotherapy. Retrospectively, 70 patients who had hormone refractory metastatic prostate cancer that were given at least 4 cycles of docetaxel chemotherapy between 2002 and 2015 were evaluated. After the onset of docetaxel, PSA response to therapy and overall survival rates were analyzed to figure out if these parameters were related to PSA doubling time. The only statistically significant prognostic parameter affecting overall survival was the best PSA response rate to docetaxel chemotherapy being over or under 50%. The most significant parameter that affects the PSA doubling time was the clinical stage at the time of diagnosis. PSA doubling time is not a useful predictive tool for predicting response to docetaxel. By means of overall survival, the clinical stage at the time of diagnosis was the best predictive tool for our cohort. The best PSA response rate to docetaxel chemotherapy was found to be a valuable parameter. The study being retrospective and the low number of patients included in this cohort can be the main weaknesses of this study. Further studies to determine which other factors can be useful are needed.

Role of prostate cancer stem-like cells in the development of antiandrogen resistance

Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer

Prostate cancer(PCa)is the second leading cause of cancer-related death in the US.Androgen receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use therapies.However,despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting,resistance mechanisms inevitably occur.Thus,novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival.Among the key cellular processes that are regulated by androgens,metabolic reprogramming stands out because of its intricate links with cancer cell biology.In this review,we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy.We describe the interplay between genetic alterations,metabolic vulnerabilities and castration resistance.Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression,we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies.We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression.We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies.Finally,we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers,and non-invasive approaches to monitor therapy response.

ADAM9 decreases in castration resistant prostate cancer and is a prognostic factor for overall survival

Background A disintegrin and metalloprotease 9 （ADAM9） is a membrane-anchored enzyme which is considered to be involved in some diseases including tumor. However, the role of ADAM9 in castration resistant prostate cancer （CRPC） is not clear. This study aimed to explore the different expressions on protein and messenger RNA （mRNA） level of ADAM9 between hormonal sensitive prostate cancer （HSPC） and CRPC tissue, and find the correlation with prognosis.

ONECUT2 as a key mediator of androgen receptorindependent cell growth and neuroendocrine differentiation in castration-resistant prostate cancer

Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.

The molecular basis for ethnic variation and histological subtype differences in prostate cancer

Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.