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Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.
Subject(s)
Male , Humans , Glutamine/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapyABSTRACT
Objective:To analyze the clinical characteristics and prognostic value of prostate-specific antigen (PSA) dynamic features in patients with metastatic castration resistant prostate cancer (mCRPC) received abiraterone acetate (AA) therapy.Methods:The data of 89 patients with mCRPC who received AA therapy from January 2017 to June 2021 in Shanghai Tongji Hospital were retrospectively reviewed. The age of patients was (75.7 ± 8.3) years old, median PSA before AA was 56.88 (19.31, 143.75) ng/ml. The PSA dynamic features included PSA nadir (PSAN) and PSAN time. PSAN was defined as the lowest value of PSA after treatment, and PSAN time was defined as time to PSAN after AA treatment. PSAN was divided into 3 groups: PSAN1 (<0.1 ng/ml), PSAN2 (0.1- 4.0 ng/ml) and PSAN3 (>4.0 ng/ml) groups. PSA response was defined as a maximum PSA decline rate ≥50%, and no PSA decline after treatment was defined as primary resistance. Cox regressions adjusted to clinical factors were performed to evaluate the influence of PSA dynamic features on patients' radiographic progression-free survival (rPFS) and overall survival (OS). Log-rank test was used to evaluate the survival time of patients in different PSAN groups. Receiver operator characteristic (ROC) curve and area under the curve (AUC) were performed to analyze the predictive value of PSA dynamic features on survival outcomes of patients.Results:The follow-up time was 17 (12, 23) months, and 75 (84.3%) patients showed PSA responses. The median PSAN was 1.82 (0.01, 11.70) ng/ml, median PSAN time was 5.0(3.0, 9.5)months. Multivariate Cox regression indicated that PSAN was an independent risk factor for rPFS ( PSAN2: HR=5.308, P=0.017; PSAN3: HR=13.209, P<0.001), and PSAN time ≥ 5 months( HR=0.309, P<0.001)was an independent protective factor for rPFS. Also, the PSAN3 was an independent risk factor for OS( HR=9.459, P=0.048). Log-rank test indicated that the rPFS of PSAN1 group (median not reached) was significantly longer than PSAN2 [median 13.0(95% CI 8.2-17.8) months, P=0.001] and PSAN3 [8.0 (95% CI 4.1-11.9) months, P<0.001] groups. ROC curve and AUC showed that PSAN had a higher predictive value in rPFS outcomes compared with T stage, metastatic disease volume, and Eastern Cooperative Oncology Group (ECOG) score (0.82 vs. 0.69, 0.68, 0.53, P<0.05). PSAN had a higher predictive value in OS outcomes than metastatic disease volume and ECOG(0.83 vs. 0.63, 0.58, P<0.05). Conclusions:Lower PSAN needs longer PSAN time. PSAN is an independent risk factor for rPFS and OS, and PSAN time is an independent protective factor for rPFS.
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Objective:To study the effect of miR-539-5p on apalutamide (ARN-509) sensitivity and malignant phenotype of androgen independent prostate cancer cell line C4-2B and related mechanisms.Methods:Castrated resistant prostate cancer, castrated sensitive prostate cancer and benign prostate tissue were obtained. C4-2B cell lines were divided into blank group, transfection group (miR-539-5p plasmid) and control group (control plasmid). qPCR was used to detect the expression of miR-539-5p, androgen receptor (AR) and HSBP1 in the tissues and 3 group of cells. The protein expressions of AR and HSBP1 were detected by western blot. Transwell assay was used to detect the invasion and migration ability of three groups of cells. CCK-8 assay was used to detect the proliferation ability and semi-inhibitory concentration (IC50) of AR antagonist ARN-509. The colony forming ability of the three groups of cells was detected by plate cloning experiment.Results:Tissue-qPCR indicated that, in the benign prostate tissue, tumor tissue of castration sensitive patients and tumor tissue of castration resistant patients, the expressions of miR-539-5p were 0.29 ± 0.04, 0.17 ± 0.02 and 0.07 ± 0.01, the expressions of AR were 0.13 ± 0.02, 0.28 ± 0.04 and 0.79 ± 0.11, and the expressions of HSBP1 were 0.20 ± 0.03, 0.38 ± 0.04 and 0.72 ± 0.11, respectively. Compared with benign prostate tissue and prostate cancer tissue, the expression of AR and HSBP1 gene was higher in prostate cancer tissues with castration resistance, and the expression of miR-539-5p was lower. Cell-qPCR demonstrated that the expressions of miR-539-5p in blank group, control group and transfection group were 1.00±0.09, 1.07±0.11 and 7.19±0.51, the expressions of AR were 1.00±0.10, 1.03±0.14 and 0.51±0.08, and the expressions of HSBP1 were 1.00±0.10, 0.96±0.12 and 0.97±0.11. The expression of miR-539-5p in the transfection cells was significantly higher than that in the control group and the blank group, the expression of AR gene was significantly lower than that in the control group and the blank group, and there was no significant difference in the expression of HSBP1. Western blot showed that, in blank group, control group and transfection group, the protein expressions of AR were 1.00±0.10, 1.12±0.22 and 0.72±0.16, and the expressions of HSBP1 were 1.00±0.10, 0.94±0.18 and 0.48±0.11. The protein expression of AR and HSBP1 in the transfection group was significantly lower than that in the control group and the blank group. Transwell experiment showed that the invasion and migration of cells in the transfection group were significantly lower than that in the control group and the blank group. CCK-8 assay and plate cloning experiment showed that the proliferative capacity and the number of clone formation in the transfection group were significantly lower than those in the control group and the blank group, and the expression of AR and HSBP1 in the transfection group was significantly lower than that in the control group and blank group. Compared with the control group and blank group, the IC50 value of ARN-509 decreased significantly in the transfection group.Conclusion:miR-539-5p may inhibit the malignant phenotype and castration resistance of cells via interfering with the translation level of HSBP1.
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Prostate cancer is one of the common malignant tumors of male urogenital system, and the incidence of prostate cancer in China has increased significantly in the past decade. At present, endocrine therapy based on androgen blockade is the main method of clinical treatment except radical surgery and radiotherapy/chemotherapy for prostate cancer. However, the clinical benefit can only be obtained in the early stage of treatment, and nearly 90% of patients will develop to the castration resistance, and among them, nearly 90% of patients will have bone metastasis. The quality of life decreases sharply with the progression of disease for patients. In addition to the androgen signal pathway, studies have shown that many other oncogenic signal pathways have involved in the development of castration resistance, including classic cancer signaling pathways, immune and inflammatory signaling pathways, etc. Understanding the mechanism of androgen independent signal pathway in the formation of castration resistance will help to understand the off-target effect of androgen blocking therapy and introduce new treatment targets or strategies to get rid of the "no drug available" dilemma for clinical treatment of castration resistance.
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@#Prostate cancer is one of the most common cancers in adult men. Heat shock proteins (HSPs),as molecular chaperones widely involved in the pathogenesis,diagnosis,treatment and prognosis of various cancers,play crucial biological functions in prostate cancer and it can be considered as valuable biomarkers for cancer therapy, such as prostate-specific membrane antigen. As a member of the heat shock protein family, HSP27 is related to prostate cancer castration resistance,and its expression can promote tumor resistance,invasion and bone metastasis,making prostate cancer more invulnerable to treatments. Therefore,targeting HSP27 in prostate cancer can be perceived as one promising cancer treatment strategy. This article reviews the structure and function of HSP27,and its potential role on castration resistance and targeted therapy in order to provide a new theoretical basis for the clinical treatment of prostate cancer.
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[Abstract] Objective To analyze the independent risk factors for castrate-resistant prostate cancer (CRPC) after conservative endocrine therapy in elderly prostate cancer patients. Methods Totally 90 elderly prostate cancer patients undergoing endocrine therapy from July 2013 to July 2015 were included into this study as research objects. The basic data and pathological, and laboratory indexes were collected from them. The incidence of CRPC in 2 years after discharge was recorded by follow-up, the Cox risk regression model was used to analyze the high-risk factors of CRPC. The application value of the risk factors to predict CRPC were analyzed by receiver operating characteristic curve and the exponential equation was established to predict the occurrence of CRPC in elderly patients with prostate cancer for 2 years. Results Totally 90 patients were followed up for 24 months in average, of whom 2 cases were lost to follow-up, 26 developed CRPC, the incidence of CRPC was 29.55%. The Cox risk regression model showed that T stage (OR=3.823, 95%CI 2.137-6.839, P<0.001), Gleason score (OR=8.045, 95%CI 3.501-18.487, P<0.001), prostatic specific antigen (PSA) (OR=2.983, 95%CI 1.407-6.324, P=0.004) and prostate cancer gene 3 (PCA3) (OR=1.998, 95%CI 1.263-3.161, P=0.003) were the independent risk factors for prostate cancer progressing to early CRPC in elderly prostate cancer patients. The exponential equation for predicting CRPC model was 0.367X1+0.642X2+0.409X3 +0.815X4 according to the results of multivariate analysis (X1: T stage, X2: Gleason score, X3: PSA value, X4: PCA3 value), the AUC was 0.855 (β=0.056, 95%CI 0.745-0.965, P<0.001). The sensitivity was 0.919, the specificity 0.857, the Youden index 0.776, and the corresponding index of prognosis 1.325. Conclusion The T stage, Gleason score, PSA and PCA3 are independent risk factors for prostate cancer progressing to CRPC after endocrine therapy in elderly prostate cancer patients, can be used comprehensively to establish a model of predicting CRPC for improving the accuracy of judgments.
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Objective To investigate the association between metabolic syndrome (MS) and castrate resistance, bone metastasis in patients with prostate cancer (PCa). Methods A total of 104 patients with PCa who underwent persistent endocrine therapy in urology department of the First Hospital of Shanxi Medical University from January 2011 to June 2015 were analyzed retrospectively. They were divided into MS and non-MS group. Combined with magnetic resonance imaging (MRI), bone scanning, prostate-specific antigen (PSA) and testosterone, the patients were followed-up for 18 months. The t test was used to compare the two groups of patients reached the castration resistance period and the occurrence of bone metastases. Results There were 35 patients in MS and 69 patients in non-MS group. There was no significant difference in age, PSA, Gleason score, staging, smoking between MS group and non-MS group (all P> 0.05); there were significant differences in body mass index (BMI), fasting blood glucose, blood pressure and blood lipid between MS group and non-MS group (all P<0.05). 16 patients in MS group progressed to castration resistant prostate cancer (CRPC) and 18 patients in non-MS group progressed to CRPC, the difference was statistically significant (χ2= 4.065, P= 0.044). MS group had 11 cases of bone metastasis and non-MS group had 11 cases of bone metastasis, and the difference was statistically significant (χ2= 4.409, P= 0.036). The survival rate of patients without CRPC in MS group and non-MS group had a significant difference (χ2=7.034, P=0.021). The survival rate of patients without bone metastasis in MS group and non-MS group also had a significant difference (χ2= 6.082, P= 0.029). Conclusions MS can promote the occurrence of CRPC and bone metastasis in PCa, which is a high risk factor in the progression of the disease. PCa patients with MS should pay attention to the diagnosis and treatment of MS related diseases, which will be better for controlling PCa.
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INTRODUCCIÓN: El cáncer de próstata (PC) es una enfermedad de alta incidencia y prevalencia (90/100.00 habitantes) y constituye la segunda causa por muerte oncológica en hombres, fenómeno que acontece en su fase metastásica (mPC). El tratamiento estándar en esta etapa corresponde a la terapia de deprivación androgénica (TDA) que produce una respuesta oncológica favorable en términos de descenso del PSA y estabilización y/o regresión de las metástasis. Ésta primera etapa (castración sensible) dura en promedio 2 a 3 años, tras lo cual ocurre una independización tumoral del estímulo androgénico, fenómeno conocido como castración-resistencia (mCRPC). En esta etapa la quimioterapia (QMT) con docetaxel prolonga la sobrevida aproximadamente 4 meses, lo cual en conjunto con otros tratamientos de segunda línea (abiraterona, enzalutamida, etc.) logra alcanzar una sobrevida media desde el diagnostico de mCRPC de 24 meses. Diversos estudios (CHAARTED y STAMPEDE) han demostrado que el inicio de docetaxel junto con TDA en pacientes con mPC castración-sensible (mCSPC) prolongan sobrevida global hasta 17 meses, especialmente si hay alto volumen de enfermedad. El objetivo del estudio es describir las características clínicas, la respuesta oncológica inicial y el perfil de efectos adversos de pacientes con mCSPC sometidos a docetaxel. MATERIALES Y MÉTODOS: Estudio retrospectivo descriptivo entre mayo 2014 a Julio 2017. Se incluyeron pacientes ng/ml (rango 10,8 - 5550) y mediana de seguimiento 6 meses (rango 3 20). Catorce pacientes tenían Gleason > 8, 18 eran M+ de los cuales 9 eran viscerales. Solo uno recibió tratamiento local previo. La mediana de inicio de QMT fue 3,1 (0 6,1) meses post inicio TDA.Dieciséis pacientes completaron docetaxel y 4 siguen en curso. No hubo suspensión de QMT por efectos adversos. Los más frecuentes fueron diarrea (8/20), neuropatía (5/20) y vómitos (2/20). La mayoría fue grado 1 y solo tres presentaron complicaciones grado 3 (diarrea, leucopenia y trombocitopenia). No hubo complicaciones grado 4 -5. Diez pacientes alcanzaron un antígeno < 2 ng/ml a las 12 semanas post tratamiento y 7 presentaron recidiva bioquímica durante el seguimiento. Uno tuvo respuesta imagenológica completa, 10 respuesta parcial, 7 estabilidad y 2 mostraron progresión. CONCLUSIONES: El uso de Docetaxel en mCSPC es seguro, presenta escasos efectos adversos (la mayoría de intensidad leve) que no motivan suspensión. El tratamiento con docetaxel exhibe una respuesta prometedora en términos de control de PSA, sin embargo se requiere mayor seguimiento de esta cohorte para evaluar impacto en sobrevida. con mCSPC con enfermedad de alto volumen (metástasis óseas extra-axiales, viscerales o Gleason 9-10) y ECOG 0-1. Los pacientes recibieron TDA y seis ciclos de Docetaxel. Se registraron datos demográficos, clínicos, histopatológicos, PSA, imagenológicos (RECIST V1.1) y toxicidad (NCI CAE 4.0) RESULTADOS: Se incluyeron 20 pacientes, mediana de edad 63 años (rango 49 75). Mediana PSA de ingreso 267,5 ng/ml (rango 10,8 - 5550) y mediana de seguimiento 6 meses (rango 3 20). Catorce pacientes tenían Gleason > 8, 18 eran M+ de los cuales 9 eran viscerales. Solo uno recibió tratamiento local previo. La mediana de inicio de QMT fue 3,1 (0 6,1) meses post inicio TDA.Dieciséis pacientes completaron docetaxel y 4 siguen en curso. No hubo suspensión de QMT por efectos adversos. Los más frecuentes fueron diarrea (8/20), neuropatía (5/20) y vómitos (2/20). La mayoría fue grado 1 y solo tres presentaron complicaciones grado 3 (diarrea, leucopenia y trombocitopenia). No hubo complicaciones grado 4 -5. Diez pacientes alcanzaron un antígeno < 2 ng/ml a las 12 semanas post tratamiento y 7 presentaron recidiva bioquímica durante el seguimiento. Uno tuvo respuesta imagenológica completa, 10 respuesta parcial, 7 estabilidad y 2 mostraron progresión. CONCLUSIONES: El uso de Docetaxel en mCSPC es seguro, presenta escasos efectos adversos (la mayoría de intensidad leve) que no motivan suspensión. El tratamiento con docetaxel exhibe una respuesta prometedora en términos de control de PSA, sin embargo se requiere mayor seguimiento de esta cohorte para evaluar impacto en sobrevida.(AU)
INTRODUCTION: Prostate cancer is a disease with high incidence and prevalence (90/100.000 habitants) and the second cause of cancer related death in men. Standard treatment in this setting is androgen-deprivation therapy (TDA), which causes decrease in PSA levels and stabilization or regression of metastatic lesions. Responses in castration sensitive phase last in average 3 years, after which tumor is described to become independent from the androgenic stimuli, reaching a castration-resistance (mCRPC) state. At this point chemotherapy with docetaxel as well as second line treatments (abiraterone, enzalutamide, among others)have shown to improve survival in 4 months with mean survival from diagnosis of mCRPC of 24 months. Studies including CHAARTED and STAMPEDE have demonstrated that early treatment with docetaxel with ADT in patients with mCSPC prolongs overall survival, especially if high volume disease exists. This study describes the clinical characteristics, initial oncologic response and side effects profile of mCSPC treated with Docetaxel plus ADT. MATERIALS AND METHODS: Descriptive Retrospective study from May 2014 to July 2017. mCSPC patients with high volume disease (extra axial bone metastasis, visceral metastasis or Gleason 9-10) and ECOG 0-1 were included. Patients received ADT and 6 cycles of Docetaxel. Demographic, clinical and histopathological characteristicswere registered, together with PSA, radiologic data (RECIST V1.1) and toxicity (NCI CAE 4.0). RESULTS: 20 patients were included, median age 63 years (49-75 range). Median initial PSA 267,5 ng/ml (10,8-5550 range), and median follow up 6 months (3-20 range). Fourteen patients had Gleason > 8, 18presented bone metastasis and 9/14 viscerametastasis. Only 1 patient received previous local treatment. Median initialtime to initiation of Docetaxel post ADT was 3,1 (0-6,1) months.Sixteen patients completed docetaxel and 4 are still receiving treatment. There was no chemotherapy suspension due side effects. Most frequent side effects were diarrhea (8/20), neuropathy (5/20) and vomiting (2/20). Most were grade 1 and three patients presented grade 3 side effects (diarrhea, leukopenia and thrombocytopenia). No grade 4-5 side effects were reported.Ten patients reached PSA< 2 ng/m after 12 weeks of treatment, and 7 had biochemical relapse during follow up. One had complete radiologic response, 10 partial response, 7 remained stable and 2 showed progression of disease. CONCLUSION: The use of docetaxel in mCSPC isassociated to few side effects and none requiredsuspension of treatment. Treatment with Docetaxel exhibits promising results in terms of decrease in PSA, however longer follow up and greater number of patients are required to report benefits in overall survival.(AU)
Subject(s)
Male , Prostatic Neoplasms , Drug Therapy , Prostatic Neoplasms, Castration-ResistantABSTRACT
Advanced prostate cancer, especially at the castration-resistant stage, remains incurable clinically and, therefore, urgently requires new therapeutics for the patients. PI3K is a family of critical cell signal transduction molecules and their over-activation is an important factor in cancer development and progression. It has been demonstrated that class IA PI3K p110 is drastically overexpressed in prostate cancer and involved in androgen receptor-mediated gene expression and castration-resistant progression and regarded as a potential therapeutic target for prostate cancer. Several p110-specific inhibitors have been reported recently and two of them, GSK2636771 and AZD8186, are being tested in clinical trials.
Subject(s)
Humans , Male , Aniline Compounds , Therapeutic Uses , Chromones , Therapeutic Uses , Imidazoles , Therapeutic Uses , Morpholines , Therapeutic Uses , Neoplasm Proteins , Phosphatidylinositol 3-Kinases , Metabolism , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Drug Therapy , Protein Kinase Inhibitors , Therapeutic UsesABSTRACT
Prostate cancer is the most prevalent male urogenital malignancy.The tumor cells are prone to castration-resistance after androgen deprivation therapy.Variation and reactivation of androgen receptor,and the change in the tumor microenvironment are the major pathological factors for development of castration-resistant prostate carcinoma (CRPC).Systematically analyzing and understanding the mechanisms for castration-resistance of prostate carcinoma will be significant for laying the basis for improvement of the strategies on precise treatment for CRPC.
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We compared the predictive ability of the 2014 and 2005 Gleason grading systems in 568 patients initially diagnosed with metastatic prostate cancer (PCA). Outcomes included the duration of castration-resistant prostate cancer-free survival (CFS) and overall survival (OS). Univariate analyses and log-rank tests were used to identify prognosis indicators and assess univariable differences in CFS and OS in Gleason score (GS) groups. Cox proportional hazards and area under the curves of receiver operator characteristics methods were used to evaluate the predictive efficacy of the 2005 and 2014 ISUP grading systems. Univariate analyses showed that the 2005 and 2014 grading systems were prognosticators for CFS and OS; both systems could distinguish the clinical outcome of patients with GS 6, GS 7, and GS 8-10. Using the 2014 criteria, no statistical differences in patient survival were observed between GS 3 + 4 and GS 4 + 3 or GS 8 and GS 9-10. The predictive ability of the 2014 and 2005 grading systems was comparable for CFS and OS (P = 0.321). However, the 2014 grading system did not exhibit superior predictive efficacy in patients initially diagnosed with PCA and bone metastasis; trials using larger cohorts are required to confirm its predictive value. To the best of our knowledge, ours is the first study to compare the 2005 and 2014 grading systems in initially diagnosed PCA with bone metastasis. At present, we recommend that both systems should be used to predict the prognosis of patients with metastatic PCA.
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Prostate cancer cells demonstrate a remarkable "addiction" to androgen receptor (AR) signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer (mCRPC). In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 (AR-V7) has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.