PURPOSE: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC).METHODS: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations.RESULTS: The panel considered peer-reviewed reports published in English.RECOMMENDATIONS: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC. Additional information is available at www.asco.org/genitourinary-cancer-guidelines

Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. In this article, we focus on reviewing the role of CD133 in PCSC. Any other main stem cell biomarkers in PCSC reported from key publications, as well as about vital research progress of CD133 in CSCs of different cancers, will be selectively reviewed to help us inform the main topic.

The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death.

Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and β-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

In this study, we investigated the potential of MIC-1 (macrophage inhibitory cytokine-1) on the severity of prostate cancer between African American men and Caucasians. Differences between the races were examined using Mann–Whitney tests for continuous variables and Fisher’s exact tests for categorical variables. Pearson’s correlation coefficient was used to identify associations between continuous measures across all samples and within each race. Analysis of variance, including clinical parameters, was used to identify differences in serum and urine MIC-1 levels between races. We found significant differences between the two races for age (p = 0.01), Gleason scores (p = 0.01), and stage of disease (p = 0.03). African American men in the study had higher Gleason scores (mean = 6.9) than Caucasians (mean = 6.5), during earlier stages of the disease. In Caucasian men with prostate cancer, serum MIC-1 expression was positively associated with age (r = 0.7, p < 0.01). However, African American men had highly expressed MIC-1 and high Gleason scores (r = 0.16, p = 0.3). Interestingly, the urine MIC-1 level was significantly higher in African American men with prostate cancer than in Caucasian patients. It appeared to be more sensitive and specific for African Americans (AUC = 0.85 vs. 0.56). Thus, high circulatory MIC-1 in prostate cancer patients may indicate MIC-1 as a potential biomarker to improve the diagnostic ability of an aggressive stage of prostate cancer in African American men. However, a larger cohort of sample analysis is required to validate these observations.