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Androgen receptor (AR) plays a key regulatory role in the development of castration resistant prostate cancer (CRPC), and the level of constitutive active variants represented by androgen receptor variant 7 (AR-V7) is increasing during the progress of CRPC, which can be used as a molecular marker of disease progress and prognosis of patients with CRPC. It is an important target to overcome castration resistance and improve the quality of life and survival of patients. In this paper, the function of AR-V7 and its molecular regulation mechanism in CRPC are reviewed. The research shows that the generation of AR-V7 is related to the structural rearrangement of AR gene, gene amplification and the selective splicing of AR gene transcripts, and it is affected by the coordinated regulation of multiple signal pathway molecules such as TGF-β; AR-V7 changes the transport and nuclear localization mechanism of AR protein, and further affects the transcriptional expression of downstream target genes. AR-V7 antagonizes AR activity and blocks the differentiation process driven by AR and androgen, and inhibits the expression of tumor suppressor genes to stimulate the proliferation of tumor cells, thus promoting the progress of Pca. Related targeting studies have revealed AR-V7 targets and CRPC treatment strategies. Currently, they mainly focus on AR-V7 protein degradation, mRNA expression inhibition and N-terminal domain targeting intervention. With the development of in-depth research, the molecular mechanism of AR-V7 in the progress of Pca will be gradually clarified, which will certainly play a greater role in the prevention and treatment of CRPC.
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【Objective】 To observe the efficacy of abiraterone (AA) in the treatment of metastatic castration-resistant prostate cancer (mCRPC). 【Methods】 The clinical data of a newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patient with high risk and high tumor load were analyzed. After operation and endocrine therapy, the disease evolution was observed. Relevant literature was reviewed. 【Results】 After laparoscopic radical prostatectomy, 6-month bicalutamide and androgen deprivation therapy (ADT), the total prostate specific antigen (tPSA) was reduced to the lowest of 0.51 ng/mL, and then increased month by month. After domestic abiraterone (trade name: Qingkeshu) in the 8th month was administered for 4 months, tPSA continued to increase to 12.39 ng/mL. The case was then diagnosed as mCRPC. The treatment was adjusted again in the 11th mouth and the patient received AA (trade name: Zeke) combined with prednisone and ADT, and tPSA decreased to 0.17 ng/mL 2 months later. After 14 months of treatment, tPSA remained at about 0.12 ng/mL. Systemic ECT examination indicated that the range of bone metastases decreased and some areas of nuclide concentration turned shallow without obvious adverse reactions. 【Conclusion】 AA combined with prednisone and ADT can produce rapid decline in PSA and a good response in mCRPC patients. It can also significantly slow the progression of bone metastasis and relieve pain symptoms without obvious adverse reactions. Long-term efficacy needs further observation.
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【Objective】 To analyze the correlation between the expressions of ZEB1, androgen receptor (AR), E-cadherin (E-Ca), N-cadherin (N-Ca) and clinicopathological features of prostate cancer patients with different risk levels, and to explore their significance. 【Methods】 The clinical data of 47 patients with prostate cancer treated during Nov.2013 and Jun.2021 were retrospectively analzyed. The patients were divided into medium-low risk group and high-risk group. The expressions of ZEB1, AR, E-Ca and N-Ca in the prostate cancer tissues of the two groups were detected with immunohistochemical staining. The relationship between the expressions and Gleason grade, prostate-specific antigen (PSA) level and TNM stage was analyzed. 【Results】 The positive expression rate of ZEB1 increased with higher risk, Gleason score, and PSA level (P<0.01); the strong positive expression rate of AR decreased with higher risk and Gleason score (P<0.05); the positive expression rate of E-Ca decreased with increased risk, Gleason score, and PSA level (P<0.05); the positive expression rate of N-Ca increased with the increased risk and Gleason score (P<0.01); the positive expression rate of ZEB1 increased with higher tumor stage and TNM stage (all P<0.01); the strong positive expression rate of AR decreased only with increased TNM stage (P<0.05). Patients whose first surgical specimen showing a higher expression level of ZEB1 were more likely to develop into castration-resistant prostate cancer CRPC (P<0.05). 【Conclusion】 ZEB1 and N-Ca levels increase with increased tumor aggressiveness, while AR and E-Ca levels decrease. ZEB1, AR, E-Ca and N-Ca play important roles in prostate cancer progression. ZEB1 can not only affect prostate cancer through epithelial stromal transformation (EMT), but also through AR. ZEB1 may also be related to the development of CRPC.
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N6-adenosine methylation, a form of methylation of the adenosine N6 site, is often found in eukaryotic mRNA and is one of the most common forms of internal RNA modification. Studies have shown that m6A affects cellular biological processes by regulating gene expression; also the regulators of m6A play a key role in the occurrence and development of various cancers. Prostate Cancer (PCa) is a common malignant tumor in men, and the risk of the disease in men over 60 years of age is increasing year by year. With the aging population, the number of PCa can be expected to continue to rise. In recent years, the role of m6A in tumorigenesis has received widespread attention, but studies on m6A methylation modification in PCa are still limited; therefore, it is particularly important to further explore the relationship between m6A methylation and PCa. In this paper, we review the recent research progress on the role, mechanism, and application of m6A methylation modification in PCa, especially the detailed review of the mechanism of METTL3, FTO, YTHDF2, three classical m6A-related regulatory proteins in PCa; and the potential application of m6A in advanced PCa (e. g., destructive resistant prostate cancer, bone metastatic prostate cancer). From the perspective of methylation modification, this paper may provide some clues to find effective therapeutic strategies for early diagnosis, treatment, and prognosis of PCa, and more theoretical references to achieve individualized treatment.
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Resumen El cáncer de próstata metastásico resistente a la castración (CPRC) es una neoplasia heterogénea letal entre los hombres. 30% de los tumores acumulan errores deletéreos en genes implicados en la respuesta al daño del ADN (DNA damage response en inglés, DDR). Algunos de estos genes asociados a cáncer son BRCA 1 y BRCA 2. Mutaciones en estos genes favorecen la pérdida o la modificación de la función provocando un cambio permanente y transmisible, lo que conduce al desarrollo de cáncer de próstata agresivo. El objetivo del estudio fue identificar mediante secuenciación dirigida (Next-generation sequencing; NGS) variantes génicas de BRCA 1 y BRCA 2 en el genoma de pacientes con CPRC del Hospital Central Militar. Es importante destacar que los resultados demostraron una serie de alteraciones clínicas, así como una pérdida de la función de las proteínas relacionadas con mecanismos de reparación del ADN. Curiosamente, algunas de las variantes en el gen BRCA, de las que se informa aquí, son de significado incierto, lo que nos ha sido comunicado por primera vez.
Abstract Metastatic castration-resistant prostate cancer (CRPC) is a heterogeneous lethal neoplasm among men. 30% of tumors harbor deleterious errors in genes involved in the DNA damage response (DDR). Some of these cancer-associated genes are BRCA 1 and BRCA 2. Mutations to these genes favor loss or modification of function causing a permanent and transmissible change, leading to the development of aggressive prostate cancer. The aim of the study was to identify by Next-generation sequencing (NGS) BRCA 1 and BRCA 2 gene variants in peripheral blood of patients with CRPC at the Hospital Central Militar. Importantly, the results demonstrated a number of clinical alterations, as well as a loss of function of proteins related to DNA repair mechanisms. Interestingly, some of the variants in the BRCA gene, reported here, are of uncertain significance, which has been reported to us for the first time.
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Objective:To investigate the risk factors for progression to castration-resistant prostate cancer (CRPC) in metastatic prostate cancer (mPCa) patients who underwent androgen deprivation therapy (ADT).Methods:One hunred mPCa patients underwent ADT were followed up from January 2014 to December 2020 in the Affiliated Central Hospital of Shenyang Medical University. Retrospective analyze the patient′s Gleason score, initial PSA value, minimum prostate specific antigen (nPSA) and time when PSA drops to the lowest point (TTN), and record the state of lymph node metastasis and bone metastasis. Single factor Kaplan-Meier analysis and multivariate Cox regression analysis were used to explore the related risk factors affecting the progress of CRPC.Results:A total of 82 cases (82%) of ADT patients progressed to CRPC. Univariate Kaplan-Meier analysis showed that Gleason score, PSA initial value, lowest nPSA and time to TTN, lymph node metastasis and bone metastasis are risk factors for CRPC ( P<0.01 or<0.05); Multivariate Cox regression analysis showed that Gleason score, initial PSA value, nPSA and TTN are independent risk factors for PCa patients to progress to CRPC ( P<0.01 or<0.05). Conclusions:This study demonstrated that Gleason score, lymph node metastasis, bone metastasis, initial PSA value, nPSA and TTN are risk factors for the progression of CRPC. Patients with higher Gleason grade, higher nPSA, shorter TTN, lymph node and bone metastasis have shorter PFS and higher risk of progression to CRPC.
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Prostate cancer is the most common male malignant tumor in the world, and its death toll is second only to lung cancer. Androgen deprivation therapy (ADT) is a major treatment for prostate cancer besides radical surgery. ADT treatment will lead to the inevitable progression of prostate cancer patients to castration-resistant prostate cancer (CRPC). The current research results have confirmed that the transformation from androgen deprivation prostate cancer (ADPC) to CRP is related to the reactivation of the androgen receptor signal pathway. In this review, the research progress on the mechanism of the androgen receptor signaling pathway in CRPC was reviewed in order to provide a scientific basis and new ideas for the diagnosis and treatment of CRP.
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DNA damage repair (DDR) defects occurred in 8%-16% of metastatic castration resistant prostate cancer (mCRPC). DDR gene mutation was related to poorer prognosis. Patients with DDR gene mutation, especially BRCA1/2 mutation, showed high sensitivity to poly ADP-ribose polymerase inhibitor (PARPi) and platinum.
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Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.
Subject(s)
Humans , Male , Abiraterone Acetate/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Androstenes , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Disease-Free Survival , Prednisone/therapeutic use , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.
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Objective:To investigate the effectiveness of surgical treatment for patients with T 4 stage prostate cancer. Methods:The clinical data and prognosis of 18 patients with T 4 stage prostate cancer treated in Shanghai Tenth People's Hospital from July 2013 to December 2019 were retrospectively analyzed. The average age of these 18 patients was 68.3 (53-81)years. 10 patients were castration resistant prostate cancer (CRPC) and 8 patients were hormone-sensitive prostate cancer (HSPC). 10 CRPC patients were treated with surgical treatment due to bladder clot packing and/or lower urinary tract obstruction. 8 HSPC patients had severe hematuria, severe dysuria and local symptoms. The KPS scores of all patients were ≥80 points with an average score of 84 (80-90). The average QOL score of 18 patients was 28 (21-32). 2 cases in 18 patients underwent total pelvic resection for rectal invasion (one CRPC and one HSPC). 7 cases underwent radical cystoprostatectomy for ureteral invasion (5 cases of CRPC, 2 cases of HSPC), 9 cases underwent bladder preservation surgery for bladder neck invasion (4 cases of CRPC, 5 cases of HSPC), of which 4 cases of enlarged lymph node dissection were all HSPC patients. Results:All cases of T 4 stage prostate cancer patients operation were successfully completed, the average operation time was 256 (219-310)min and the median intraoperative blood loss was about 300 (250-350)ml. Four of them (3 cases of CRPC and 1 case of HSPC) received blood transfusion after operation. The average postoperative hospital stay was 21(11-37) days. All 18 cases were followed up and the median follow-up time was 23.8 months. There was no perioperative death, and no bladder-preserving patients had true urinary incontinence or bladder outlet stenosis.2 CRPC cases died 8 and 15 months after surgery respectively, 7 patients were PSA relapse treated with docetaxel or abiterone therapy, and 1 HSPC patient with rectal invasion was followed up for 58 months after total pelvic resection, the PSA level was still 0.003ng/ml, no distant metastasis was found. 8 cases of hormone-sensitive patients were treated with endocrine therapy, and PSA was less than 0.2 ng/ml. The average QOL of 18 patients 3 months after operation was 37 points (25-45), which was significantly higher than that before operation. The average maximum urine flow rate of patients with bladder preservation was 23(19-25)ml/s. Conclusions:For T 4 stage prostate cancer, surgical treatment is feasible and safe for doctors with extensive surgical experience. For CRPC patients, the surgery can significantly improve short-term symptoms and quality of life, and long-term benefits need to be further evaluated with a large sample. For HSPC patients, it can not only improve clinical symptoms and QOL of patients, but also provide long-term benefits.
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Objective:To investigate the characteristics of 18F-DCFPyL PET/CT imaging in castration-resistant prostate cancer (CRPC) patients with different PSA levels. Methods:The imaging and clinical data of 50 patients with CRPC who underwent 18F-DCFPyL PET/CT examination in Chinese PLA General Hospital from January 2018 to December 2020 were analyzed retrospectively. The average age was 72 (54-95) years old. Serum total PSA was 92.28(0.36-2000.00) ng/ml. According to the total PSA level, the patients were divided into low PSA group(total PSA ≤ 1 ng/ml, n=9), medium PSA group (1 ng/ml<total PSA ≤ 10 ng/ml, n=18) and high PSA group(total PSA>10ng/ml, n=23). According to the standardized evaluation standard of molecular imaging, the suspicious tumor lesions on 18F-DCFPyL PET/CT imaging were scored by molecular imaging PSMA(miPSMA), and the miPSMA score ≥2 was defined as positive lesions. According to the number of lesions displayed by 18F-DCFPyL PET/CT, patients were divided into oligofocal group (the number of lesions ≤3) and multiple lesions group (the number of lesions >3). The imaging characteristics of patients in different groups were summarized. Results:The 18F-DCFPyL PET/CT imaging results of 50 cases in this study were all positive, including oligofocal group (n=27) and multiple lesions group (n=23). Of the 30 patients with unresected prostate, 18 had local recurrence of the prostate, while the other 12 patients with unresected prostate and 20 patients with resected prostate had no signs of local recurrence. The oligofocal group showed local recurrence, regional lymph node metastasis or bone metastasis. Patients with multiple lesions showed multiple lymph nodes and/or bone metastasis with or without local recurrence. There were 9, 18 and 4 patients with oligofoci in low, middle and high PSA groups, respectively.There were 27 patients in the oligonucleogenous group, and 21 of the 22 patients receiving local treatment were effective. All 3 patients treated with systemic treatments were effective. PSA progressed in 2 untreated patients. In the multi-foci group of 23 patients, 6 of 9 patients treated with abiraterone were effective. Two patients treated with enzalumide were ineffective. One of the 4 patients with chemotherapy was effective. One of the two patients treated with 177 Lu-PSMA nuclide was effective. One case did not respond to treatment with 89SrCl 2. Radiotherapy failed in 2 cases. PSA progressed in 3 untreated patients. Conclusions:18F-DCFPyLPET/CT imaging has a high detection rate of lesions in patients with CRPC and has potential guiding significance for follow-up treatment. The number of lesions in CRPC patients with different PSA levels was different, and the patients with low PSA levels were mainly oligofoci.
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Objective:To explore the efficacy and mechanism of Guben Qingyuan prescription combined with androgen deprivation therapy （ADT） in the treatment of castration-resistant prostate cancer （CRPC）. Method:A CRPC-bearing mouse model was established. When the tumor volume reached about 100 mm<sup>3</sup>， 50 CRPC-bearing BALB/c nude mice were randomly divided into the model group， ADT group， and ADT+low-， medium-， high-dose Guben Qingyuan prescription groups， with 10 mice in each group. After grouping， it was ensured that there was no statistically significant difference in tumor volume between groups. The mice in the model group was treated with the same amount of normal saline （10 mL·kg<sup>-1</sup>） by gavage， twice a day， while those in the other groups were provided with bicalutamide （5 mg·kg<sup>-1</sup>） for intragastric administration， once a day， and then with goserelin （0.36 mg·kg<sup>-1</sup>） for intraperitoneal injection on the 10th day. On the basis of ADT， the ones in the ADT+Guben Qingyuan prescription groups further received Guben Qingyuan prescription at the low （2.5 g·kg<sup>-1</sup>）， medium （25 g·kg<sup>-1</sup>）， and high doses （50 g·kg<sup>-1</sup>） by gavage， twice a day. After 25 days of continuous administration， the tumor tissue was harvested for recording the tumor growth and calculating the tumor inhibition rate. The mRNA and protein expression levels of androgen receptor （AR）， androgen receptor splice variant-7 （AR-V7）， and prostate-specific antigen （PSA） were detected by real-time polymerase chain reaction （Real-time PCR） and Western blot assay. Result:The tumor inhibition rates of the ADT+low-， medium-， and high-dose Guben Qingyuan prescription groups were 27.95%， 46.71%， and 44.46%， respectively， and the inhibition rates in the ADT+medium- and high-dose Guben Qingyuan prescription groups were significantly increased as compared with that in the ADT group （<italic>P</italic><0.05）. As revealed by comparison with the ADT group， Guben Qingyuan prescription at the medium and high doses significantly down-regulated the mRNA and protein expression levels of AR， AR-V7， and PSA （<italic>P</italic><0.05）. Conclusion:Guben Qingyuan prescription combined with ADT is efficient in controlling the tumor growth in CRPC-bearing mice， which is related to the regulation of AR/AR-V7 signaling pathway.
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As the end-stage of prostate cancer, metastatic castration-resistant prostate cancer(mCRPC) complicates the disease and therefore challenges the doctors. In October 2018, an 87-year-old patient diagnosed with metastatic prostate cancer was admitted to Shanghai General Hospital for evaluation and treatment. Poor basic health condition plus severe side effect resulted in patient’s poor compliance with treatment and irregular follow-up. The patient progressed to mCRPC in September 2020, and was given enzalutamide as first-line therapy, after which the patient’s PSA level was under control with no side effect.
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Metastatic castration-resistant prostate cancer (mCRPC) is the inevitable form of most prostate cancers after endocrine therapy, and conventional drugs are not effective at this time.In this case, an elderly mCRPC patient with cardiopulmonary diseases admitted to the First Hospital of Shanxi Medical University in August 2020 was selected. After the failure of traditional endocrine therapy, enzalumide+ ADT regimen was adopted, and the patient's blood PSA was significantly reduced without cardiopulmonary adverse events.
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This case was a 75-year-old prostate cancer patient with multiple cardiovascular diseases. The clinical stage was T 3bN 1M 0.After regular follow-up with androgen deprivation therapy (ADT)(Goserelin+ bicalutamide), the PSA increased slowly at the 13th month, and at the 17th month, the trend of progression to castrated resistant prostate cancer (CRPC) was considered, combined with patients with a variety of cardiovascular diseases, we choose the first-line application of Enzaluamine treatment, the disease has been effectively controlled. Through the diagnosis and treatment of this case, we should consider not only the effectiveness and safety of the treatment, but also the influence and risk of the treatment to the cardiovascular disease.
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AIM: To study the correlation between the expression of recepteur d'origine nantais (RON) protein and CXC chemokine motif receptor 4 (CXCR4) protein and abiraterone resistance in patients with castration-resistant prostate cancer (CRPC). METHODS: From January 2017 to February 2020, 127 patients with CRPC who were treated with abiraterone in our hospital were selected. According to the status of drug resistance, they were divided into observation group (n=32, patients with abiraterone resistance) and control group (n=95, patients in remission). Immunohistochemistry and Western blot analysis were used to compare the expression of RON and CXCR4 protein between the two groups. Logistic regression analysis was used to conduct single-factor and multi-factor analysis of RON, CXCR4 protein and drug resistance, and receiver operating characteristic curve (ROC) and area under ROC (AUC) were used to analyze the value of RON and CXCR4 protein in predicting drug resistance. In addition, RON and CXCR4 inhibitors were added to abiraterone-resistant cell lines. The effects of the two on the apoptosis indicators of abiraterone resistance[caspase-3, caspase-9, apoptosis rate] were observed. RESULTS: Immunohistochemistry showed that the positive expression rate of RON in the observation group (71.88%, 23/32) was higher than that of the control group (27.37%, 26/95). The positive expression rate of CXCR4 in the observation group (65.63%, 21/32) was higher than that of the control group (12.63%, 12/95). Western blot detection showed that the RON and CXCR4 proteins in the observation group were higher than those in the control group (P 4.11, the sensitivity was 84.37%, and the specificity was 61.05% (P 3.42, the sensitivity was 75.00%, and the specificity was 80.00% (P< 0.05). The AUC of RON+CXCR4 protein predicting abiraterone resistance was 0.884 (95%CI: 0.815-0.934), the sensitivity was 87.50%, and the specificity was 83.16% (P< 0.05). CONCLUSION: The expression of RON and CXCR4 protein in CRPC patients increases significantly, which is closely related to the resistance of Abiraterone in patients and is expected to become a marker for predicting drug resistance. Inhibiting the expression of RON and CXCR4 proteins can promote the apoptosis of CRPC abiraterone resistant cells.
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【Objective】 To screen nucleic acid aptamers that can specifically recognize castration-resistant prostate cancer （CRPC） cells by Cell-SELEX. 【Methods】 For Cell-SELEX selection， CRPC cell lines C4-2 were used as positive control cells， while androgen-dependent prostate cancer cell lines LNCap were used as negative control cells. The 5’end of the upstream primers was labeled with FITC， and the 5’end of the downstream primers was labeled with biotin. Single-stranded DNA （ssDNA） collected from each round of screening was used as template for PCR amplification and purification. The biotin-streptavidin magnetic bead separation was used to isolate PCR product for the next round of screening. The process of Cell-SELEX was analyzed by flow cytometry. ssDNA products of the last round were collected for PCR amplification， purification， cloning and DNA sequencing. The secondary structure of selected DNA aptamers was predicted. Dissociation constants of the two aptamers were calculated. Flow cytometry and confocal microscopy were used to evaluate selective binding of aptamers to CRPC cells and tissues. 【Results】 The binding rate of DNA products to CRPC cells gradually increased with the increase of selection cycles， reaching the highest in the last round. DNA structure prediction analysis showed that the secondary structure of aptamers CRPC-1 and CRPC-2 was mainly stem-loop structure. Flow cytometry analysis and confocal images showed that both CRPC-1 and CRPC-2 could specifically target C4-2 cells. In addition， immunohistofluorescence assay showed that CRPC-1 could specifically target CRPC tissues. 【Conclusion】 Cell-SELEX can be used to screen aptamers that specifically target CRPC cells and tissues， which provides experimental basis for early screening and targeted diagnosis of CRPC. It is of significance for treatment plan adjustment and prognosis improvement of prostate cancer.
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Eastern Cooperative Oncology Group (ECOG) performance status and Gleason score are commonly investigated factors for overall survival (OS) in men with castration-resistant prostate cancer (CRPC). However, there is a lack of consistency regarding their prognostic or predictive value for OS. Therefore, we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories. A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019. The data from 8247 patients in 34 studies, including clinical trials and real-world data, were included in our meta-analysis. Of these, twenty studies reported multivariate results and were included in our main analysis. CRPC patients with higher ECOG performance statuses (≥ 2) had a significantly increased mortality risk than those with lower ECOG performance statuses (<2), hazard ratio (HR): 2.10, 95% confidence interval (CI): 1.68-2.62, and P < 0.001. The synthesized HR of OS stratified by Gleason score was 1.01, with a 95% CI of 0.62-1.67 (Gleason score ≥ 8 vs <8). Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy (docetaxel and cabazitaxel) and androgen-targeting therapy (abiraterone acetate and enzalutamide) or for patients with different chemotherapy histories. ECOG performance status was identified as a significant prognostic factor in CRPC patients, while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.
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Background and Aims: CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC. Materials and Methods: Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS). Results: A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750–0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557–0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517–0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo. Conclusion: This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs