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 a...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.展开更多
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 t...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.展开更多
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 c...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.展开更多
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 ac...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 “pre-metastatic niche model”, 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.展开更多
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 ass...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.展开更多
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(A...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.展开更多
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 heterogenei...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.展开更多
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 r...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.展开更多
Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We ...Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake via TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche,such as bone.Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy,we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development.The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers,MMPs,and transcription factors such as Twist,Snail,and Slug.Moreover,TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes.In vivo,mice bearing trpv6^(+/+)tumors presented increased metastasis,notably bone metastasis,whereas trpv6^(−/−)mice developed no metastasis.Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival.When AMD3100,a selective inhibitor of the CXCR4 receptor,was combined with AMD3100,a synergistic effect on the suppression of metastasis development was achieved.Thus,the suppression of CRPC metastasis to bone can be achieved via simultaneous targeting of TRPV6/CXCR4,demonstrating that combined therapy is a proof-of-concept approach in vivo.展开更多
Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-a...Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-assembly nanotechnology,we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect.Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor,utilizing the spatial distance self-adaptive characteristics of its nanostructure.In the 22Rv1 cell model,Nano-PROTAC degraded 80%of the AR protein and 65%of the HSP90 protein.More importantly,nano-PROTAC could degrade 74%of the AR splice variant AR-V7 protein,showing the potential ability to overcome drug resistance.We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC.Compared with the combination treatment group of AR and HSP90 inhibitors(enzalutamide and pimitespib),the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78%and a median survival extension of 15 days.Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA-and AR-positive castration-resistant prostate cancer,except for neuroendocrine prostate cancer,which provides a new therapeutic strategy for the treatment of prostate cancer.展开更多
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 ...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.展开更多
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 abiratero...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.展开更多
Multidrug-resistant prostate cancer,particularly castration-resistant prostate cancer,remains a marked therapeutic challenge because of poor drug bioavailability,systemic toxicity,and resistance mechanisms.Nanoparticl...Multidrug-resistant prostate cancer,particularly castration-resistant prostate cancer,remains a marked therapeutic challenge because of poor drug bioavailability,systemic toxicity,and resistance mechanisms.Nanoparticle-based codelivery systems improve targeted drug accumulation,stability,and controlled release within the tumor microenvironment.The complementary mechanisms of action of these agents include paclitaxel-induced mitotic arrest and apoptosis,and chrysin increases cytotoxicity by modulating oxidative stress,suppressing survival pathways,and overcoming drug resistance.Preclinical studies have demonstrated superior efficacy and reduced toxicity compared with those of monotherapies.Despite promising results,formulation challenges,regulatory barriers,and scalability issues must be addressed to translate this dual-drug strategy into clinical applications.Overall,the codelivery of paclitaxel-chrysin via nanocarriers represents a promising advance in the personalized treatment of resistant prostate cancer.展开更多
基金This work is supported in part by grants NIH/NCI CA140468,CA168601,CA179970,DOD PC130062,Ralph de Vere White endowment,US Department of Veterans Affairs,Office of Research and Development VA Merits I01 BX002653by resources from the VA Northern California Health Care System,Sacramento,California.
文摘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.
文摘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.
基金This study was supported by grants from Shanghai Cancer Center Foundation, the Natural Science Foundation of China （No. 30973009）, and the Shanghai National Natural Science Foundation （No. 1 lZR1407400）
文摘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.
文摘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 “pre-metastatic niche model”, 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.
基金We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program.The investigators Drs.Robert Vessella,Bruce Montgomery,Evan Yu,Heather Cheng,Elahe Mostaghel,Paul Lange,and Martine Roudier for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Programhis research was supported by funding by the Pacific Northwest Prostate Cancer SPORE(P50CA97186),R01CA165573the Richard M.LUCAS Foundation.Colm Morrissey is a recipient of a Career Development Award from Jim and Catherine Allchin.
文摘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.
基金This work was supported by NIH(CA106504,CA169524)and DOD(W81XWH-15-1-0612)grants to YQThe authors apologize for not being able to cite many important studies related to this subject due to limited space.
文摘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.
文摘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.
文摘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.
基金supported by the French“Ligue Contre le Cancer”.
文摘Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake via TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche,such as bone.Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy,we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development.The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers,MMPs,and transcription factors such as Twist,Snail,and Slug.Moreover,TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes.In vivo,mice bearing trpv6^(+/+)tumors presented increased metastasis,notably bone metastasis,whereas trpv6^(−/−)mice developed no metastasis.Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival.When AMD3100,a selective inhibitor of the CXCR4 receptor,was combined with AMD3100,a synergistic effect on the suppression of metastasis development was achieved.Thus,the suppression of CRPC metastasis to bone can be achieved via simultaneous targeting of TRPV6/CXCR4,demonstrating that combined therapy is a proof-of-concept approach in vivo.
基金supported by the National Natural Science Foundation of China(52322308,52273126)the National Key R&D Program of China(2022YFA1205700,2022YFE0200800)the Beijing Nova Program(20240484673,20230484237).
文摘Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-assembly nanotechnology,we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect.Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor,utilizing the spatial distance self-adaptive characteristics of its nanostructure.In the 22Rv1 cell model,Nano-PROTAC degraded 80%of the AR protein and 65%of the HSP90 protein.More importantly,nano-PROTAC could degrade 74%of the AR splice variant AR-V7 protein,showing the potential ability to overcome drug resistance.We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC.Compared with the combination treatment group of AR and HSP90 inhibitors(enzalutamide and pimitespib),the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78%and a median survival extension of 15 days.Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA-and AR-positive castration-resistant prostate cancer,except for neuroendocrine prostate cancer,which provides a new therapeutic strategy for the treatment of prostate cancer.
文摘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.
基金Efforts are supported by the Department of Defense Grant(W81XWH-18-1-0618 and W81XWH-19-1-0720)to Gupta S.Kushwaha PP acknowledges financial support from University Grants Commission,India in the form of CSIR-UGC Senior Research fellowshipKumar S acknowledges University Grants Commission,India+2 种基金Department of Science and Technology,India for providing financial support in the form of UGC-BSR Research Start-Up-Grant[F.30-372/2017(BSR)]DST-SERB Grant(EEQ/2016/000350)respectively.Kumar S acknowledges Central University of Punjab,Bathinda,India for providing Research Seed Money Grant(GP-25)Singh AK,Prajapati KS,and Shuaib M acknowledge CSIR-India,DBT-India and DST-India funding agencies respectively for providing financial assistance in the form of Junior Research Fellowship.
文摘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.
文摘Multidrug-resistant prostate cancer,particularly castration-resistant prostate cancer,remains a marked therapeutic challenge because of poor drug bioavailability,systemic toxicity,and resistance mechanisms.Nanoparticle-based codelivery systems improve targeted drug accumulation,stability,and controlled release within the tumor microenvironment.The complementary mechanisms of action of these agents include paclitaxel-induced mitotic arrest and apoptosis,and chrysin increases cytotoxicity by modulating oxidative stress,suppressing survival pathways,and overcoming drug resistance.Preclinical studies have demonstrated superior efficacy and reduced toxicity compared with those of monotherapies.Despite promising results,formulation challenges,regulatory barriers,and scalability issues must be addressed to translate this dual-drug strategy into clinical applications.Overall,the codelivery of paclitaxel-chrysin via nanocarriers represents a promising advance in the personalized treatment of resistant prostate cancer.
