Dingwei Ye

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration‐resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen‐deprivation therapy in patients with newly diagnosed, metastatic, castration‐sensitive prostate cancer. Methods In this double‐blind, placebo‐controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen‐deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250‐mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen‐deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression‐free survival. Results After a median follow‐up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression‐free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate‐specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. Conclusions The addition of abiraterone acetate and prednisone to androgen‐deprivation therapy significantly increased overall survival and radiographic progression‐free survival in men with newly diagnosed, metastatic, castration‐sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285.)

Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy.

miR‐21 has been recognized as an “onco‐microRNA” with the activity of negatively modulating the expression of tumor‐suppressor genes. However, its role in prostate cancer (CaP) has not been well‐documented. We designed this study to assess the potential function of serum miR‐21 in the progression of CaP.

Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells.

AbstractAim:To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.Methods:A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.Results:A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.Conclusion:Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.

A multiplex model of combining gene‐based, protein‐based, and metabolite‐based with positive and negative markers in urine for the early diagnosis of prostate cancer

Multiplex urine‐based assay emerged outperforms single biomarker (e.g., prostate‐specific antigen, PSA) for predicting prostate cancer (CaP), whereas its combined mode has to be fully optimized. Our aim is to determine whether a strategy of combining gene‐based, protein‐based, metabolite‐based with positive, negative makers in urine could optimize a multiplex model for detecting CaP.

Constitutively Active AR-V7 Plays an Essential Role in the Development and Progression of Castration-Resistant Prostate Cancer

This study aimed to investigate the role of AR-V7 in development of castration-resistant prostate cancer (CRPC) and to determine whether the AR-V7 expression in CRPC tissues can predict cancer-specific survival. We enrolled 100 localized prostate cancer (PCa) (cohort 1), 104 newly diagnosed metastatic PCa (cohort 2), and 46 CRPC (cohort 3) patients treated at our institution. The expression of AR-V7 in PCa was assessed by immunohistochemistry. Cox regression models were used to evaluate the predictive role of all covariates for the development of CRPC in cohort 2 and for cancer-specific survival in cohort 3. Time to CRPC and cancer-specific survival curves were estimated using the Kaplan-Meier method. AR-V7 expression rate in cohort 3 was significantly elevated compared with other two cohorts (p < 0.001). Multivariate analysis revealed that AR-V7 was an independent predictive factor for CRPC development (HR = 2.627, p = 0.001) and for cancer specific survival (HR = 2.247, p = 0.033). Furthermore, the AR-V7 expression was associated with shorter survival in CRPC patients. Our results demonstrated protein AR-V7 levels in primary tumors can be used as a predictive marker for the development of CRPC and as a prognostic factor in CRPC patients. Therapy targeting AR-V7 may help prevent PCa progression and improve the prognosis of CRPC patients.

Predicting Pelvic Lymph Node Metastases in Penile Cancer Patients: A Comparison of Computed Tomography, Cloquet’s Node, and Disease Burden of Inguinal Lymph Nodes

Background: The aim of this study was to evaluate the role of computed tomography (CT), Cloquet’s node, and disease burden of inguinal lymph nodes (LNs) in predicting pelvic lymph node metastases (LNM) of penile cancer. Patients and Methods: Bilateral inguinal lymph node dissection was performed in 73 penile cancer patients and revealed that 33 groin basins exhibited inguinal LNM. Results: Of the 33 groin basins, 16 (48.5%) had pelvic LNM. The sensitivity of pelvic CT in detecting metastatic LNs was 37.5%, and the specificity was 100%. Cloquet’s node had a sensitivity of 30.0% and a specificity of 94.1% in pelvic CT-negative groin basins. Pathological characteristics of the inguinal LNs - number of positive LNs, lymph node ratio (number of positive LNs/total number removed), extranodal extension and the expression of p53 - were significantly associated with pelvic LNM. Furthermore, enlarged inguinal LNs = 3 in preoperative CT imaging and lymph node size = 3.5 cm in long diameter were prognostic factors for pelvic LNM (p = 0.001 and 0.003, respectively). Conclusion: Pelvic CT imaging and tumor status of Cloquet’s node is of limited use in predicting microscopic pelvic LNM. Pathological characteristics of the inguinal LNs remain the essential indicators of pelvic LNM.

Efficacy of sorafenib on metastatic renal cell carcinoma in Asian patients: results from a multicenter study.

BackgroundThe effects of sorafenib in the treatment of advanced renal cell carcinoma (RCC) have been confirmed in an international collaborative phase III trial. This study aims to confirm similar efficacy and treatment-induced toxicities of sorafenib in the treatment of metastatic RCC in ethnic Chinese patients.MethodsNinety-eight consecutive and non-selected patients with pathologically confirmed metastatic RCC were treated according to an institutional treatment protocol. All patients were treated with 400 mg of sorafenib orally twice daily on a continuous basis until disease progression or intolerance to treatment occurred. Dose reduction to 400 mg once daily was required if grade 3 or 4 toxicities occurred. All patients except for 7 received nephrectomy in the course of their disease. All patients were assessed for tumor response, progression-free survival (PFS), overall survival (OS), and treatment-induced toxicities.ResultsThe median follow-up time was 76 weeks (range 2–296 weeks) for the entire group of patients. Radiologically confirmed complete response (CR), partial response (PR), stable disease (SD) of more than 4 months, and disease progression as best objective responses were observed in 1 (1%), 23 (23.5%), 62 (63.3%), and 12 (12.2%) patients, respectively. The tumor control rate (CR+PR+SD of >4 months) was 87.8%. The 1-year estimated PFS and OS were 58.4% and 64.6%, respectively. The median progression-free survival (PFS) time was 60 weeks (95% CI 41–79); and the median overall survival (OS) time was not reached with a follow-up of 76 weeks. Reduction of sorafenib dose was required in 26 patients who developed grade 3 or 4 treatment-cause adverse-effects. An additional 9 patients discontinued sorafenib treatment due to severe adverse-effects. No grade 5 toxicity occurred.Multivariate analysis revealed that independent predictive factors for tumor response to sorafenib treatment included ECOG status, presence of lymph node metastasis, and nephrectomy prior to the development of metastasis.ConclusionSorafenib produced an 87.8% disease control rate for metastatic renal cell carcinoma in Chinese patients, with acceptable rates of toxicity. The medication dosed at 400 mg twice daily is both efficacious and safe in the treatment of metastatic renal cell carcinoma in Chinese patients.

Activation of the mammalian target of rapamycin signalling pathway in prostate cancer and its association with patient clinicopathological characteristics

To evaluate the activation level of the mammalian target of rapamycin (mTOR) signalling pathway in Chinese patients with prostate cancer, as this pathway is over‐activated in many human cancers and is an attractive target for cancer therapy.

External validation of a nomogram using RENAL nephrometry score to predict high grade renal cell carcinoma.

PURPOSE A novel nomogram using the RENAL ([R]adius maximal diameter in cm, [E]xophytic/endophytic properties, [N]earness of the tumor to the collecting system or sinus in mm, [A]nterior/Posterior, [L]ocation relative to the polar lines and [H]ilar) nephrometry score was developed to predict high grade renal cell carcinoma. It showed good performance in internal evaluation. We externally validated the prediction model. MATERIALS AND METHODS We identified a cohort of 391 Chinese patients in whom renal cell carcinoma was surgically resected at our institution from 2008 to 2011. Fuhrman grade was reviewed by an experienced genitourinary pathologist and radiological images were independently assessed by 2 senior urologists. Using a 2-tiered system high grade disease was defined as Fuhrman grade III/IV. The statistical performance of the prediction model was evaluated by discrimination, calibration and clinical usefulness. RESULTS Of the 391 patients 45.5% were considered to have high grade tumors. External validation of the nomogram revealed an AUC of 0.73. The calibration plot showed that the predicted probability of high grade disease had concordance comparable to the observed frequency. On decision curve analysis the prediction model provided a superior net benefit and reduction at a greater than 20% probability threshold. CONCLUSIONS We confirm the predictive value of the nomogram using the RENAL nephrometry score to identify high grade renal cell carcinoma in an independent cohort. Further research is required to evaluate its performance using a head-to-head comparison with renal biopsy results.

NADP+-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance

Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1(R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors.