Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

Studies have suggested that statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) medication use may decrease prostate specific antigen in healthy men. We determined the effect of preoperative statin use on total preoperative prostate specific antigen and the risk of biochemical recurrence in patients with prostate cancer presenting for radical prostatectomy. A retrospective review of 3,828 patients undergoing radical prostatectomy from January 2001 to July 2008 at our institution identified 1,031 on statin medications. We compared these 1,031 patients to the remaining 2,797 not on statins preoperatively. We evaluated differences in prostate specific antigen overall, and when patients were stratified by age specific groups, body mass index and Gleason grades on final pathology. We also investigated differences in biochemical recurrence rates. Overall median serum prostate specific antigen was lower in patients on preoperative statins (5.0 vs 5.2 ng/ml, p = 0.002). Median prostate specific antigen was lower in men on statins with Gleason grades 7 or 8/9 disease (p <0.05). Using a multivariate logistic regression model statin therapy was associated with a 4.7% decrease in prostate specific antigen (p <0.001). Statin therapy was not associated with an overall decreased risk of biochemical recurrence (p = 0.73) at a mean followup of 26 months. In this cohort of men presenting for radical prostatectomy serum prostate specific antigen is significantly lower in patients with prostate cancer on preoperative statins compared to those not taking these medications. Prospective studies are required to evaluate if this decrease in prostate specific antigen leads to later detection of prostate cancer or variations in oncological outcomes.

Background: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. Methods: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. Results: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi’s ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth. Conclusions: Tipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.

Prostate cancer is the most common malignancy in American men following skin cancer, with approximately one in eight men being diagnosed during their lifetime. Over the past several decades, the treatment of prostate cancer has evolved rapidly, so too has screening. Since the mid-2010s, magnetic resonance imaging (MRI)–guided biopsies or ‘targeted biopsies’ has been a rapidly growing topic of clinical research within the field of urologic oncology. The aim of this publication is to provide a review of biparametric MRI (bpMRI) utilization for the diagnosis of prostate cancer and a comparison to multiparametric MRI (mpMRI). Through single-centered studies and meta-analysis across all identified pertinent published literature, bpMRI is an effective tool for the screening and diagnosis of prostate cancer. When compared with the diagnostic accuracy of mpMRI, bpMRI identifies prostate cancer at comparable rates. In addition, when omitting dynamic contrast-enhanced (DCE) protocol to the MRI, patients incur reduced costs and shorter imaging time while providers can offer more tests to their patient population.