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BACKGROUND: In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy. OBJECTIVE: To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by 64 CuCl2 PET scan. Intravenous (IV) CuCl2 was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro. RESULTS: We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on 64 CuCl2 PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro. CONCLUSIONS: Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.
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Neoplasias Peritoneais , Neoplasias de Próstata Resistentes à Castração , Cobre/uso terapêutico , Dissulfiram/uso terapêutico , Humanos , Masculino , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.
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Acetato de Abiraterona , Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Humanos , Masculino , Prednisona/efeitos adversos , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.
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Biomarcadores Tumorais , DNA Tumoral Circulante , Variação Genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Genômica/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/patologia , Fenótipo , Prognóstico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/terapia , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Humanos , Indazóis , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Radium-223 improves survival and time to first symptomatic skeletal event in symptomatic bone predominant metastatic castrate-resistant prostate cancer (mCRPC). The imaging response to radium-223 has not been well characterized. METHODS: To describe patterns of response and progression with radium-223, we performed a retrospective review of all mCPRC patients who received radium-223 at Duke from 1 June 2013 to 1 June 2015. Radionuclide bone scans obtained at baseline, during, and after treatment were reviewed by two radiologists. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI version 2.4. Computed tomography (CT) and magnetic resonance imaging (MRI) clinical radiology reports were reviewed to evaluate for soft tissue, visceral, epidural, and bone progression. Clinical data were abstracted from the electronic health record. RESULTS: We identified 61 men who received at least one dose of radium-223 at Duke during the study period (median, 5 doses; range, 1-6). Among men with imaging during treatment, 2 of 14 (14.3%) had resolution of greater than or equal to 1 lesion on bone scan, 4 of 14 (28.6%) had zero new bone lesions, 10 of 14 (71.4%) had greater than or equal to 1 new bone lesion, 14 of 26 (53.9%) progressed on CT. After radium-223, 6 of 39 (15.4%) had resolution of 1 to 4 bone lesions, 15 of 39 (38.5%) demonstrated zero new bone lesions, 24 of 39 (61.5%) progressed on bone scan, 15 of 37 (40.5%) progressed on CT, and 10 of 34 (29.4%) progressed on both bone scan and CT. No men with zero new bone lesions after radium-223 ultimately progressed in bone alone and only 3 of 15 eventually demonstrated any progression in the bone. aBSI decreased significantly from baseline to after radium-223 among men with zero new bone lesions (median change in aBSI -0.23 [IQR, -1.5, 0.02]) and increased significantly for men with greater than or equal to 1 new postradium bone lesions (median change in aBSI 1.41 [IQR, -0.05, 3.63] [P = 0.018]). CONCLUSIONS: Bone and soft tissue progression during and following radium-223 is common in heavily pretreated men with mCRPC. However, stable disease and responses were observed in a subset of patients and may be associated with durable treatment response in the bone. Prospective studies are needed to further investigate the change in aBSI as a biomarker of bone scan response/stabilization and progression following treatment with radium-223.
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Neoplasias Ósseas/radioterapia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Neoplasias de Tecidos Moles/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Neoplasias de Tecidos Moles/secundário , Resultado do TratamentoRESUMO
We investigated the intersection of epidermal growth factor receptor (EGFR) and CCAAT enhancer binding protein (C/EBP)-ß signaling in glioblastoma (GBM), given that both gene products strongly influence neoplastic behavior. C/EBP-ß is known to drive the mesenchymal transcriptional signature in GBM, likely through strong microenvironmental influences, whereas the genetic contributions to its up-regulation in this disease are not well described. We demonstrated that stable overexpression and activation of WT EGFR (U87MG-WT) led to elevated C/EBP-ß expression, as well as enhanced nuclear translocation and DNA-binding activity, leading to up-regulation of C/EBP-ß transcription and translation. Deeper investigation identified bidirectional regulation, with C/EBP-ß also causing up-regulation of EGFR that was at least partially dependent on the STAT3. Based on ChIP-based studies, we also found that that the translational isoforms of C/EBP-ß [liver-enriched transcription-activating protein (LAP)-1/2 and liver inhibitory protein (LIP)] have differential occupancy on STAT3 promoter and opposing roles in transcriptional regulation of STAT3 and EGFR. We further demonstrated that the shorter C/EBP-ß isoform, LIP, promoted proliferation and migration of U87MG glioma cells, potentially via induction of cytokine IL-6. Our molecular dissection of EGFR and C/EBP-ß pathway interactions uncovered a complex signaling network in which increased activity of either EGFR or C/EBP-ß leads to the up-regulation of the other, enhancing oncogenic signaling. Disrupting the EGFR-C/EBP-ß signaling axis could attenuate malignant behavior of glioblastoma.-Selagea, L., Mishra, A., Anand, M., Ross, J., Tucker-Burden, C., Kong, J., Brat, D. J. EGFR and C/EBP-ß oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-ß isoform.
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Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Receptores ErbB/metabolismo , Regulação da Expressão Gênica/fisiologia , Glioma/metabolismo , Transdução de Sinais , Células Cultivadas , Glioma/genética , Humanos , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia , Transcrição Gênica/genética , Ativação Transcricional/fisiologiaRESUMO
BACKGROUND: Depression is a global mental disorder, and traditional diagnostic methods mainly rely on scales and subjective evaluations by doctors, which cannot effectively identify symptoms and even carry the risk of misdiagnosis. Brain-Computer Interfaces inspired deep learning-assisted diagnosis based on physiological signals holds promise for improving traditional methods lacking physiological basis and leads next generation neuro-technologies. However, traditional deep learning methods rely on immense computational power and mostly involve end-to-end network learning. These learning methods also lack physiological interpretability, limiting their clinical application in assisted diagnosis. METHODOLOGY: A brain-like learning model for diagnosing depression using electroencephalogram (EEG) is proposed. The study collects EEG data using 128-channel electrodes, producing a 128×128 brain adjacency matrix. Given the assumption of undirected connectivity, the upper half of the 128×128 matrix is chosen in order to minimise the input parameter size, producing 8,128-dimensional data. After eliminating 28 components derived from irrelevant or reference electrodes, a 90×90 matrix is produced, which can be used as an input for a single-channel brain-computer interface image. RESULT: At the functional level, a spiking neural network is constructed to classify individuals with depression and healthy individuals, achieving an accuracy exceeding 97.5â¯%. COMPARISON WITH EXISTING METHODS: Compared to deep convolutional methods, the spiking method reduces energy consumption. CONCLUSION: At the structural level, complex networks are utilized to establish spatial topology of brain connections and analyse their graph features, identifying potential abnormal brain functional connections in individuals with depression.
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Interfaces Cérebro-Computador , Depressão , Eletroencefalografia , Redes Neurais de Computação , Humanos , Eletroencefalografia/métodos , Depressão/fisiopatologia , Depressão/diagnóstico , Encéfalo/fisiopatologia , Encéfalo/fisiologia , Aprendizado Profundo , Modelos Neurológicos , Adulto , Potenciais de Ação/fisiologiaRESUMO
Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.
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Herein we continue the study of matrix metalloproteinase-1 (MMP-1) with respect to glioblastoma multiforme (GBM) cell tumorigenicity and angiogenesis. A model of tumorigenicity with cells stably altered to over-express or knock-down MMP-1 revealed that it significantly increases tumor incidence and size. Organized endothelial growth in human umbilical vein endothelial cell (HUVEC)-GBM co-cultures was significantly increased in the presence of MMP-1. CD31 analysis of model tumors elucidated a substantial recruitment of endothelium in MMP-1 enhanced samples. Antibody arrays indicated an inverse expression of certain anti-angiogenic factors with respect to MMP-1, the most notable of which was a significant increase in tissue inhibitor of metalloproteinases-4 (TIMP-4) in the absence of MMP-1, as validated by immunoblot.
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Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Metaloproteinase 1 da Matriz/genética , Inibidores Teciduais de Metaloproteinases/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais/patologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Nus , Mutação/genética , Neovascularização Patológica/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteômica , Inibidores Teciduais de Metaloproteinases/genética , Veias Umbilicais/citologia , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
Elongation factor eEF3 is an ATPase that, in addition to the two canonical factors eEF1A and eEF2, serves an essential function in the translation cycle of fungi. eEF3 is required for the binding of the aminoacyl-tRNA-eEF1A-GTP ternary complex to the ribosomal A-site and has been suggested to facilitate the clearance of deacyl-tRNA from the E-site. Here we present the crystal structure of Saccharomyces cerevisiae eEF3, showing that it consists of an amino-terminal HEAT repeat domain, followed by a four-helix bundle and two ABC-type ATPase domains, with a chromodomain inserted in ABC2. Moreover, we present the cryo-electron microscopy structure of the ATP-bound form of eEF3 in complex with the post-translocational-state 80S ribosome from yeast. eEF3 uses an entirely new factor binding site near the ribosomal E-site, with the chromodomain likely to stabilize the ribosomal L1 stalk in an open conformation, thus allowing tRNA release.
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Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/metabolismo , RNA de Transferência/metabolismo , Saccharomyces cerevisiae/química , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Proteínas Fúngicas/ultraestrutura , Regulação Fúngica da Expressão Gênica , Modelos Biológicos , Modelos Moleculares , Fatores de Alongamento de Peptídeos/ultraestrutura , Conformação Proteica , Ribossomos/química , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. METHODS: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. RESULTS: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. CONCLUSIONS: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.
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COVID-19 , Carcinoma Neuroendócrino , Neoplasias da Próstata , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Pandemias , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Neuroendócrino/patologiaRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. METHODS: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. RESULTS: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. CONCLUSIONS: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. GOV IDENTIFIER: NCT02256111.
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Antagonistas de Androgênios , Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Androgênios , Benzamidas , Terapia por Exercício , Humanos , Masculino , Recidiva Local de Neoplasia , Nitrilas , Orquiectomia , Feniltioidantoína , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Qualidade de VidaRESUMO
Men with circulating tumor cell (CTC) AR-V7-positive metastatic castration-resistant prostate cancer (mCRPC) have worse outcomes when treated with enzalutamide/abiraterone. However, most men lack CTC AR-V7 detection, and additional predictive biomarkers are needed. We conducted a retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men with mCRPC undergoing treatment with enzalutamide/abiraterone, analyzing pooled CTC and germline DNA for whole-genome copy-number alterations (CNA) in 73 samples from 48 men over time along with pooled CTC and germline whole-exome sequencing on 22 paired samples before and following progression on androgen receptor (AR) inhibitor therapy to identify somatic genomic alterations associated with acquired resistance. We observed broad interpatient and longitudinal CTC genomic heterogeneity from AR-V7-negative men with mCRPC, including common gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN. Men who had progression-free survival of ≤3 months despite enzalutamide/abiraterone treatment were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC. After progression on abiraterone/enzalutamide, we observed clonal evolution of CTCs harboring TP53 mutations and gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2. CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). IMPLICATIONS: We identified common and reproducible genomic alterations in CTCs from AR-V7-negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Genômica/métodos , Células Neoplásicas Circulantes/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Benzamidas/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control. METHODS AND MATERIALS: This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life. RESULTS: We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months. CONCLUSIONS: The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.
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Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Idoso , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Intervalos de Confiança , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Qualidade de Vida , Glândulas Seminais/efeitos da radiação , Testosterona/sangue , Fatores de TempoRESUMO
BACKGROUND: Salvage external beam radiotherapy (RT) with androgen deprivation therapy (ADT) improves survival over RT in men with prostate cancer (PC) and rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP). OBJECTIVE: To investigate the safety and efficacy of enzalutamide concurrent with salvage RT and ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a three-center prospective phase 2 single-arm trial (NCT02057939) of men with Gleason 7-10 PC and PSA recurrence within 4 yr of RP ranging from 0.2 to 4.0 ng/dl, no prior hormonal therapy, and no radiographic evidence of metastases. We enrolled 38 men; 37 completed therapy and were evaluable with testosterone recovery at 2 yr. INTERVENTION: Six months of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was improved 2-yr progression-free survival (PFS) over historical controls. Secondary objectives included 3-yr PFS, safety, and patient-reported quality of life (QOL). RESULTS AND LIMITATIONS: The primary endpoint of 2-yr PFS was 65% (95% confidence interval [CI]: 47, 78) versus 51% (95% CI: 33, 67) in a trial of men with similar eligibility treated with salvage RT and adjuvant docetaxel. The 3-yr PFS was 53%. Eleven (29%) men experienced G3 toxicities, and there were no G4-5 or unexpected toxicities. QOL data suggest modest worsening of bowel, bladder, and hormonal symptoms at 3 mo, with recovery by 24 mo in most men. CONCLUSIONS: Salvage RT with enzalutamide and ADT following RP for men with PSA recurrent high-risk PC is safe and demonstrates encouraging efficacy, warranting prospective controlled phase 3 trials of ADT with or without potent androgen receptor inhibition in this curative-intent setting. PATIENT SUMMARY: Addition of 6 mo of oral daily enzalutamide to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 yr.
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Infarto do Miocárdio , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Androgênios , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias da Próstata/tratamento farmacológico , Qualidade de VidaRESUMO
BACKGROUND: A subset of men with metastatic prostate cancer (mPC) responds to immune checkpoint inhibitors, and there is an unmet need to predict those most likely to benefit. We characterized circulating tumor cells (CTCs) for expression of immune checkpoint ligands in men with mPC as a non-invasive biomarker of immune evasion and immunotherapy benefit. METHODS: Three cohorts of patients were enrolled: 1) men with mCRPC starting abiraterone acetate/prednisone or enzalutamide (pre-ARSI), 2) men with mCRPC who were progressing on enzalutamide or abiraterone acetate/prednisone (post-ARSI), and 3) men with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy. CTCs were captured using the CellSearch® system and stained for PD-L1, PD-L2, B7-H3, and CTLA-4 at baseline, on treatment, and disease progression. Summary statistics on mean CTCs per cohort, as well as rates of ligand positivity were used to analyze CTCs by cohort and by timepoint. RESULTS: Men in all cohorts and timepoints had prevalent CTC B7-H3 expression (> 80%). We found evidence for CTC PD-L1 expression across disease states, in which > 1 positive CTC or > 50% of CTCs were positive for PD-L1 in 40 and 30% of men with mHSPC, respectively, 60 and 20% of men with mCRPC pre-ARSI, and 70 and 30% of men with mCRPC post-ARSI. CTC PD-L2 expression was present in 20-40% of men in each disease state, while CTC CTLA-4 expression was rare, present in 20% of men with mCRPC pre-ARSI and 10% of men with mCRPC post-ARSI or with mHSPC. CTC immune checkpoint expression was heterogeneous within/between men and across disease states. CONCLUSIONS: We have identified that CTCs from men with mPC heterogeneously express immune checkpoints B7-H3, PD-L1, PD-L2, and CTLA-4, and the detection of these immune checkpoints may enable monitoring on immunotherapy.
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PURPOSE: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. EXPERIMENTAL DESIGN: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). RESULTS: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6-12.7). CONCLUSIONS: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.
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Androstenos/uso terapêutico , Benzamidas/uso terapêutico , Instabilidade Cromossômica , Células Neoplásicas Circulantes , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sistemas Neurossecretores , Fenótipo , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Activation of the PI3K-Akt-mTOR signaling pathway is common in advanced castration resistant prostate cancer (CRPC), typically through PTEN loss. Preclinical studies suggest that Akt-driven CaP cells are genetically susceptible to mammalian target of rapamycin (mTOR, or TORC1) inhibition. Everolimus is a Food and Drug Administration-approved inhibitor of TORC1. MATERIALS AND METHODS: We performed a phase II study of everolimus in patients with mCRPC, who were refractory to standard of care hormonal and chemotherapeutic agents. Patients received everolimus 10 mg daily until unacceptable adverse events or disease progression. The primary efficacy outcome was confirmed 50% or greater prostate-specific antigen (PSA) response, using a 2 stage design with futility rules. Paired biopsies were utilized to assess for treatment effect on downstream TORC1 targets as well as tumor cell proliferation and apoptosis. RESULTS: Out of 35 men enrolled with heavily pretreated mCRPC, 32 were evaluable for clinical efficacy. No PSA responses were observed, the median progression-free survival time was 3.6 months (95% confidence intervalâ¯=â¯2.9-4.8) and the median overall survival time was 10.4 months (95% confidence intervalâ¯=â¯5.8-15.8). Several patients had declines in serum PSA upon cessation of everolimus. Thus, the study was closed due to clinical futility. The most common toxicities were mucositis, fatigue, anorexia, hypertriglyceridemia, and thrombocytopenia and were largely low grade. Pathologic evaluation of paired metastatic biopsies demonstrated consistent inhibition of pS6, a downstream mTOR pharmacodynamics biomarker, but the tumor proliferation marker Ki-67 increased with therapy. CONCLUSIONS: Everolimus demonstrated predictable toxicity in advanced and heavily pretreated patients with mCRPC. No clinical or clear pathologic effects despite downstream TORC1 target inhibition, suggesting that single agent everolimus has no clinical utility in men with mCRPC.
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Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/secundário , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
PURPOSE: Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy. PATIENTS AND METHODS: PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points. RESULTS: We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors. CONCLUSION: Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.
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PURPOSE: Nuclear factor-kappaB (NF-kappaB) is constitutively expressed in many acute myelogenous leukemia (AML) cells and AML stem cells. Ex vivo treatment of AML cells with inhibitors of NF-kappaB results in diminished AML cell survival and enhances the cytotoxic effects of chemotherapeutic agents. The purpose of this study was to determine if standard anti-inflammatory agents modulate AML cell nuclear NF-kappaB when administered in conjunction with induction chemotherapy. EXPERIMENTAL DESIGN: Patients with newly diagnosed AML were treated with dexamethasone, choline magnesium trisalicylate, or both for 24 hours prior to and 24 hours following initiation of standard induction chemotherapy. AML cell nuclear NF-kappaB was measured at baseline, 24, and 48 hours. RESULTS: Choline magnesium trisalicylate +/- dexamethasone decreased nuclear NF-kappaB, whereas dexamethasone alone was associated with an increase in nuclear NF-kappaB in AML cells. CONCLUSIONS: These results show the feasibility of NF-kappaB modulation in conjunction with induction chemotherapy for patients with AML using inexpensive readily available medications. A follow-up study to determine the effects of NF-kappaB modulation on clinical end points is warranted.