Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 919
Filtrar
1.
Medicine (Baltimore) ; 99(15): e19760, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282738

RESUMO

BACKGROUND: In recent years, metastatic castration-resistant prostate cancer (MCRPC) and studies related to MCRPC have drawn global attention. The main objective of this bibliometric study was to provide an overview of MCRPC, explore clusters and trends in research and investigate the future direction of MCRPC research. METHODS: A total of 4089 publications published between 1979 and 2018 were retrieved from the Web of Science (WoS) Core Collection database. Different aspects of MCRPC research, including the countries/territories, institutions, journals, authors, research areas, funding agencies and author keywords, were analyzed. RESULTS: The number of annual MCRPC publications increased rapidly after 2010. American researchers played a vital role in this increase, as they published the most publications. The most productive institution was Memorial Sloan Kettering Cancer Center. De Bono, JS (the United Kingdom [UK]) and Scher, HI (the United States of America [USA]) were the two most productive authors. The National Institutes of Health (NIH) funded the largest number of published papers. Analyses of keywords suggested that therapies (abiraterone, enzalutamide, etc.) would attract global attention after US Food and Drug Administration (FDA) approval. CONCLUSIONS: Developed countries, especially the USA, were the leading nations for MCRPC research because of their abundant funding and frequent international collaborations. Therapy was one of the most vital aspects of MCRPC research. Therapies targeting DNA repair or the androgen receptor (AR) signing pathway and new therapies especially prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) would be the next focus of MCRPC research.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/secundário , Publicações/normas , United States Food and Drug Administration/organização & administração , Androstenos/uso terapêutico , Bibliometria , Neoplasias Ósseas/secundário , Reparo do DNA/efeitos dos fármacos , Humanos , Masculino , Metástase Neoplásica , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Publicações/tendências , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
3.
Bull Cancer ; 107(4): 506-516, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32145961

RESUMO

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Raras/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Acetato de Abiraterona/uso terapêutico , Fatores Etários , Idoso , Anilidas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Previsões , Humanos , Mutação , Nitrilos/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prognóstico , Doenças Raras/tratamento farmacológico , Transdução de Sinais , Compostos de Tosil/uso terapêutico
5.
Crit Rev Oncol Hematol ; 146: 102864, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31986318

RESUMO

Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium-223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the possible reasons why different radium-based combination treatments can led to different clinical outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/uso terapêutico , Rádio (Elemento)/uso terapêutico , Androstenos/uso terapêutico , Neoplasias Ósseas/secundário , Docetaxel/uso terapêutico , Humanos , Masculino , Orquiectomia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Radioisótopos/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral
8.
Mol Carcinog ; 59(1): 62-72, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674708

RESUMO

Prostate cancer (PCa) deaths are typically the result of metastatic castration-resistant PCa (mCRPC). Recently, enzalutamide (Enz), an oral androgen receptor inhibitor, was approved for treating patients with mCRPC. Invariably, all PCa patients eventually develop resistance against Enz. Therefore, novel strategies aimed at overcoming Enz resistance are needed to improve the survival of PCa patients. The role of exosomes in drug resistance has not been fully elucidated in PCa. Therefore, we set out to better understand the exosome's role in the mechanism underlying Enz-resistant PCa. Results showed that Enz-resistant PCa cells (C4-2B, CWR-R1, and LNCaP) secreted significantly higher amounts of exosomes (2-4 folds) compared to Enz-sensitive counterparts. Inhibition of exosome biogenesis in resistant cells by GW4869 and dimethyl amiloride strongly decreased their cell viability. Mechanistic studies revealed upregulation of syntaxin 6 as well as its increased colocalization with CD63 in Enz-resistant PCa cells compared to Enz-sensitive cells. Syntaxin 6 knockdown by specific small interfering RNAs in Enz-resistant PCa cells (C4-2B and CWR-R1) resulted in reduced cell number and increased cell death in the presence of Enz. Furthermore, syntaxin 6 knockdown significantly reduced the exosome secretion in both Enz-resistant C4-2B and CWR-R1 cells. The Cancer Genome Atlas analysis showed increased syntaxin 6 expressions associated with higher Gleason score and decreased progression-free survival in PCa patients. Importantly, IHC analysis showed higher syntaxin 6 expression in cancer tissues from Enz-treated patients compared to Enz naïve patients. Overall, syntaxin 6 plays an important role in the secretion of exosomes and increased survival of Enz-resistant PCa cells.


Assuntos
Antineoplásicos/farmacologia , Exossomos/metabolismo , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Proteínas Qa-SNARE/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Exossomos/efeitos dos fármacos , Humanos , Masculino , Feniltioidantoína/farmacologia , Neoplasias da Próstata/metabolismo
9.
Prostate ; 80(1): 99-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742767

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunotoxinas/efeitos adversos , Imunotoxinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Taxa de Sobrevida , Resultado do Tratamento
10.
Prostate ; 80(3): 256-266, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31856338

RESUMO

BACKGROUND: Because androgen receptor (AR) signaling is essential for prostate cancer (PCa) initiation and progression, castration is the main approach for treatment. Unfortunately, patients tend to enter a stage called castration-resistant prostate cancer (CRPC) despite the initial response to castration. For various reasons, AR signaling is reactivated in CRPC. As such, AR signaling inhibitors, such as enzalutamide, has been approved by the Food and Drug Administration to treat CRPC in the clinic. However, the limited success of these new drugs suggests an immediate unmet need to understand the underlying mechanisms for resistance so novel targets can be identified to enhance their efficacy. METHODS: An unbiased bioinformatics analysis was performed with the existing human patient dataset and RNA-seq results of in-house PCa cell lines to identify new targets to overcome enzalutamide resistance. Cell viability and growth were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and colony formation assay. Cell invasion and migration were detected by transwell assay. Protein levels were detected by Western blot or immunofluorescence. RESULTS: We found that the noncanonical Wnt signaling was activated in enzalutamide-resistant PCa cells and that the activation of noncanonical Wnt signaling was correlated with AR expression and disease progression. This was validated by the elevated expression of noncanonical Wnt pathway members such as Wnt5a, RhoA, and ROCK in enzalutamide-resistant PCa cells in comparison to their enzalutamide-sensitive counterparts. And, both Y27632, an inhibitor of ROCK, and depletion of ROCK enhanced the efficacy of enzalutamide in enzalutamide-resistant PCa cells. Of significance, a combination of Y27632 and enzalutamide inhibited 22RV1-derived xenograft tumor growth synergistically. Finally, ROCK depletion plus enzalutamide treatment inhibited invasion and migration of enzalutamide-resistant PCa cells via inhibition of epithelial-mesenchymal transition. CONCLUSIONS: The noncanonical Wnt pathway is activated in enzalutamide-resistant PCa and inhibition of noncanonical Wnt pathway overcomes enzalutamide resistance and enhances its efficacy in CRPC.


Assuntos
Amidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Piridinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Amidas/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Piridinas/administração & dosagem , Distribuição Aleatória , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
13.
Semin Oncol ; 46(4-5): 351-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31757478

RESUMO

BACKGROUND: With 1.3 million new cases in 2018 worldwide, prostate cancer remains a challenge. Development of novel therapies targeting the androgen pathway followed recognition of the continued importance of androgens in castrate-resistant prostate cancer. To assess abiraterone and enzalutamide efficacy we analyzed data from US Veterans Administration Medical Centers (VAMCs). METHODS: We used a novel method independent of assessment intervals and ideal for real-world analysis to estimate rates of tumor growth (g) and regression (d). FINDINGS: Using the VA Informatics and Computing Infrastructure, we collected data from 5,116 Veterans with castrate-resistant prostate cancer prescribed abiraterone, enzalutamide or both. We estimated values for g and d and demonstrated a correlation of g with overall survival (P < .0001). Abiraterone and enzalutamide slowed growth rates across age groups and across the entire VAMC system, although less so in Veterans previously treated with a taxane and those with Gleason grade group 5 tumors. Abiraterone and enzalutamide efficacy in first-line were comparable although abiraterone in first-line slowed growth rates significantly more in African Americans than in Caucasians; enzalutamide was a better salvage therapy. When abiraterone was first-line and g was low, switching to enzalutamide was associated with a faster g in 67%. INTERPRETATION: In the real-world g can be estimated using a novel analysis method indifferent to assessment intervals that correlates highly with OS. While we show excellent real-world outcomes with abiraterone and enzalutamide, 2 effective and tolerable therapies, our results in VAMCs suggest enzalutamide should follow abiraterone. Changing therapies may be detrimental and consideration should be given to continue monitoring of growth rates over time. Funding Support from the Prostate Cancer Foundation and the Blavatnik Family Foundation.


Assuntos
Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/terapia , Saúde dos Veteranos , Veteranos , Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Humanos , Masculino , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/patologia , Resultado do Tratamento , Estados Unidos/epidemiologia , Saúde dos Veteranos/estatística & dados numéricos
14.
Medicine (Baltimore) ; 98(44): e17748, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689828

RESUMO

BACKGROUND: Previous evidence directly evaluating the efficacy and safety of abiraterone and enzalutamide treatment for castration-resistant prostate cancer (CRPC) is limited. We aim to include more randomized controlled trials (RCTs) to comprehensively assess the efficacy and safety of abiraterone and enzalutamide treatment. METHODS: PubMed, Embase, and ClinicalTrial.gov were systematically searched. Pooled hazard ratios (HRs) were calculated using Stata 12.0 software. The comparison of the prostate-specific antigen (PSA) response rate and adverse events (AEs) between the treatment and control groups were performed using RevMan 5.3 software. RESULTS: Eight eligible RCTs with 6,490 patients were selected. Pooled HRs were 0.72 for overall survival, 0.45 for radiographic progression-free survival (rPFS), and 0.36 for PSA PFS. abiraterone and enzalutamide could significantly increase the PSA response rate OR = 8.67, 95%CI 4.42-17.04) and any AE occurrence (OR = 1.98, 95%CI 1.46-2.68). The treatment group had more occurrence of fatigue (OR = 1.34, 95%CI 1.20-1.49), back pain (OR = 1.15, 95%CI 1.01-1.15), hot flush (OR = 1.76, 95%CI 1.50-2.06), diarrhea (OR=1.22, 95%CI 1.07-2.40) and arthralgia (OR = 1.34, 95%CI 1.16-1.54). Particularly, AEs of special interest including any grade hypertension (OR = 2.06, 95%CI 1.71-2.47), hypokalemia (OR = 1.80, 95%CI 1.42-2.30) and fluid retention or edema (OR = 1.38, 95%CI 1.17-1.63) also occurred less in the control group. Moreover, a higher incidence of high-grade hypertension (OR = 2.60, 95%CI 1.79-3.79) and extremity pain (OR = 4.46, 95%CI 2.81-7.07) was observed in the treatment group. CONCLUSION: The survival benefits of abiraterone and enzalutamide for CRPC were evident and promising, while the risk of AE occurrence was also acceptably higher in the treatment group than in the placebo group.


Assuntos
Androstenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
N Engl J Med ; 381(26): 2506-2518, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31566937

RESUMO

BACKGROUND: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear. METHODS: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed. RESULTS: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed. CONCLUSIONS: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).


Assuntos
Antagonistas de Androgênios/administração & dosagem , Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Androstenos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Prednisona/administração & dosagem , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA