<span style="font-family:Verdana;">Enzalutamide is a hormonal therapy that blocks the action of androgens, such as testosterone in the treatment of metastatic castration-resistant prostate cancer. <...<span style="font-family:Verdana;">Enzalutamide is a hormonal therapy that blocks the action of androgens, such as testosterone in the treatment of metastatic castration-resistant prostate cancer. </span><span style="font-family:Verdana;">Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) overlap and are part of an adverse drug reaction continuum of disease, in which there is a 10% - 30% involvement of the skin surface with mucositis, blisters, skin slough, and a macular rash. A 66-year-old male was treated with enzalutamide for metastatic prostate cancer and developed SJS/TEN overlap with 25% total body surface area skin involvement. The patient received a </span><span style="font-family:Verdana;">seven-day course of cyclosporine to which he responded by re-epithelialization </span><span style="font-family:Verdana;">but succumbed to multi-organ failure. While SJS/TEN has been reported with apalutamide, to our knowledge, this is the first case of SJS/TEN overlap with enzalutamide.</span>展开更多
A novel route of enzalutamide was developed in five steps.Starting from 4-amino-2-(trifluoromethyl)benzonitrile(7)and Boc-2-aminoisobutyric acid(16),condensation,deprotection,Ullmann coupling,cyclization and amination...A novel route of enzalutamide was developed in five steps.Starting from 4-amino-2-(trifluoromethyl)benzonitrile(7)and Boc-2-aminoisobutyric acid(16),condensation,deprotection,Ullmann coupling,cyclization and amination provided enzalutamide in 41.0%total yield.This route avoids the using of toxic chemical,unstable intermediate and high-risk reaction.It is a potential efficient and economical procedure for industrialization.展开更多
Recent studies revealed the relationship among homologous recombination repair(HRR),androgen receptor(AR),and poly(adenosine diphosphate-ribose)polymerase(PARP);however,the synergy between anti-androgen enzalutamide(E...Recent studies revealed the relationship among homologous recombination repair(HRR),androgen receptor(AR),and poly(adenosine diphosphate-ribose)polymerase(PARP);however,the synergy between anti-androgen enzalutamide(ENZ)and PARP inhibitor olaparib(OLA)remains unclear.Here,we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines.Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining(NHEJ)and apoptosis pathways.ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit(DNA-PKcs)and X-ray repair cross complementing 4(XRCC4).Moreover,our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor(IGF1R)and the upregulation of pro-apoptotic gene death-associated protein kinase 1(DAPK1).Collectively,our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects,providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.展开更多
This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A lit...This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR. 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR. 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.展开更多
An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and ...An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity.Five identified impurities were also synthesized.This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations,which is suitable for further industrialization.展开更多
Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. H...Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.展开更多
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
There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunothe...There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.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
Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(...Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.展开更多
The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is no...The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal.Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel,abiraterone acetate,enzalutamide,apalutamide,and/or radiotherapy to the primary tumour.As a result,these approaches are now included in treatment guidelines and considered standard of care.However,the different treatment strategies have not been directly compared,and thus treatment selection remains at the discretion of the individual physician or,ideally,a multidisciplinary team.Given the range of available treatment approaches with varying toxicity profiles,treatment selection should be individualized based on the patient’s clinical characteristics and preferences,which implies active patient participation in the decision-making process.In the present document,we discuss the changing landscape of the management of patients with metastatic hormonesensitive prostate cancer in the context of several recently-published landmark randomized trials.In addition,we discuss several unresolved issues,including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.展开更多
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 intratumo...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.展开更多
Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize wi...Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize with enzalutamide,a second-generation AR inhibitor,in TNBC.By using a strategy for screening drug combinations based on the Sensitivity Index(SI),we found that MK-8776,a selective checkpoint kinase1(CHK1)inhibitor,showed favorable synergism with enzalutamide in AR-positive TNBC.The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776,respectively.Furthermore,a nanoparticle-based on hyaluronic acid(HA)-modified hollow-manganese dioxide(HMnO_(2)),named HMnE&M@H,was established to encapsulate and deliver enzalutamide and MK-8776.This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness.HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier.Collectively,our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H,providing a potential therapeutic approach for the treatment of TNBC.展开更多
In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in pro...In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway.Among these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients.Unfortunately,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant phenotype.Although the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling pathways.Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR signalling.In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.展开更多
Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abirat...Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abiraterone acetate,a P450c17 inhibitor,and enzalutamide,a potent AR antagonist.However,drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months.Multiple mechanisms can contribute to ARSI drug resistance.These mechanisms can include but are not limited to germline mutations in the AR,post-transcriptional alterations in AR structure,and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor.This review focuses on intracrine androgen biosynthesis,how this can contribute to ARSI drug resistance,and therapeutic strategies that can be used to surmount these resistance mechanisms.展开更多
文摘<span style="font-family:Verdana;">Enzalutamide is a hormonal therapy that blocks the action of androgens, such as testosterone in the treatment of metastatic castration-resistant prostate cancer. </span><span style="font-family:Verdana;">Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) overlap and are part of an adverse drug reaction continuum of disease, in which there is a 10% - 30% involvement of the skin surface with mucositis, blisters, skin slough, and a macular rash. A 66-year-old male was treated with enzalutamide for metastatic prostate cancer and developed SJS/TEN overlap with 25% total body surface area skin involvement. The patient received a </span><span style="font-family:Verdana;">seven-day course of cyclosporine to which he responded by re-epithelialization </span><span style="font-family:Verdana;">but succumbed to multi-organ failure. While SJS/TEN has been reported with apalutamide, to our knowledge, this is the first case of SJS/TEN overlap with enzalutamide.</span>
基金supported by Scientific Research Cadre Project(AMSCP)2021National Key Research and Development Program of China(No.2020YFA0509200 to C.Sheng)。
文摘A novel route of enzalutamide was developed in five steps.Starting from 4-amino-2-(trifluoromethyl)benzonitrile(7)and Boc-2-aminoisobutyric acid(16),condensation,deprotection,Ullmann coupling,cyclization and amination provided enzalutamide in 41.0%total yield.This route avoids the using of toxic chemical,unstable intermediate and high-risk reaction.It is a potential efficient and economical procedure for industrialization.
基金This work was supported by the National Natural Science Foundation of China(82002718)the Jiangsu Natural Science Foundation(BK20191077)Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University)Clinical Capacity Enhancement Project(JSPH-MC-2021-12).
文摘Recent studies revealed the relationship among homologous recombination repair(HRR),androgen receptor(AR),and poly(adenosine diphosphate-ribose)polymerase(PARP);however,the synergy between anti-androgen enzalutamide(ENZ)and PARP inhibitor olaparib(OLA)remains unclear.Here,we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines.Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining(NHEJ)and apoptosis pathways.ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit(DNA-PKcs)and X-ray repair cross complementing 4(XRCC4).Moreover,our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor(IGF1R)and the upregulation of pro-apoptotic gene death-associated protein kinase 1(DAPK1).Collectively,our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects,providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.
文摘This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR. 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR. 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.
基金the 2016 Shanghai Pujiang Talent program (No. 16PJ1432800)China State Institute of Pharmaceutical Institute Industry for financially supporting this program
文摘An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity.Five identified impurities were also synthesized.This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations,which is suitable for further industrialization.
基金supported by the National Natural Science Foundation of China (Nos. 81903656 and 81673468)the National Key New Drug Innovation Program, the Ministry of Science and Technology of China (No. 2018ZX09201017-006)+3 种基金Natural Science Foundation of Jiangsu Province (No. BK20180560, China)China Postdoctoral Science Foundation (No. 2018M632430)“Double First-Class” University project (Nos. CPU2018GF10 and CPU2018GY46, China)the Scientific Startup Foundation for High level Scientists of China Pharmaceutical University (No. 3154070026, China)
文摘Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.
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There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.
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.
文摘Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.
文摘The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal.Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel,abiraterone acetate,enzalutamide,apalutamide,and/or radiotherapy to the primary tumour.As a result,these approaches are now included in treatment guidelines and considered standard of care.However,the different treatment strategies have not been directly compared,and thus treatment selection remains at the discretion of the individual physician or,ideally,a multidisciplinary team.Given the range of available treatment approaches with varying toxicity profiles,treatment selection should be individualized based on the patient’s clinical characteristics and preferences,which implies active patient participation in the decision-making process.In the present document,we discuss the changing landscape of the management of patients with metastatic hormonesensitive prostate cancer in the context of several recently-published landmark randomized trials.In addition,we discuss several unresolved issues,including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.
文摘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.
基金supported by the Key INTERNATIONAL COOPERATION of the National Natural Science Foundation of China(No.81920108029,China)the Key Foundation for Social Development Project of the Jiangsu Province,China(No.BE2021741,China).
文摘Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize with enzalutamide,a second-generation AR inhibitor,in TNBC.By using a strategy for screening drug combinations based on the Sensitivity Index(SI),we found that MK-8776,a selective checkpoint kinase1(CHK1)inhibitor,showed favorable synergism with enzalutamide in AR-positive TNBC.The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776,respectively.Furthermore,a nanoparticle-based on hyaluronic acid(HA)-modified hollow-manganese dioxide(HMnO_(2)),named HMnE&M@H,was established to encapsulate and deliver enzalutamide and MK-8776.This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness.HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier.Collectively,our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H,providing a potential therapeutic approach for the treatment of TNBC.
文摘In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway.Among these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients.Unfortunately,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant phenotype.Although the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling pathways.Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR signalling.In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.
基金This work was supported by the National Institute of Environmental Health Science(P30ES013508)(to Penning TM)by DoD Idea Development grant from the National Cancer Institute(W81XWH-17-1-0404 and R01CA249210)(Asangani IA)and by Department of Defense Prostate Cancer Research Program(W81XWH-17-1-0484,W81XWH-17-2-0323,W81XWH-20-1-0146),Lopker Foundation,Institute for Prostate Cancer Research,and Veterans Affairs Research Program(to Sprenger C and Plymate S).
文摘Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abiraterone acetate,a P450c17 inhibitor,and enzalutamide,a potent AR antagonist.However,drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months.Multiple mechanisms can contribute to ARSI drug resistance.These mechanisms can include but are not limited to germline mutations in the AR,post-transcriptional alterations in AR structure,and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor.This review focuses on intracrine androgen biosynthesis,how this can contribute to ARSI drug resistance,and therapeutic strategies that can be used to surmount these resistance mechanisms.