KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach.

BACKGROUND: There remains a need to identify and validate biomarkers for predicting prostate cancer (CaP) outcomes using robust and routinely available pathology techniques to identify men at most risk of premature death due to prostate cancer. Previous immunohistochemical studies suggest the proliferation marker Ki67 might be a predictor of survival, independently of PSA and Gleason score. We performed a validation study of Ki67 as a marker of survival and disease progression and compared its performance against another candidate biomarker, DLX2, selected using artificial neural network analysis. METHODS: A tissue microarray (TMA) was constructed from transurethral resected prostatectomy histology samples (n=192). Artificial neural network analysis was used to identify candidate markers conferring increased risk of death and metastasis in a public cDNA array. Immunohistochemical analysis of the TMA was carried out and univariate and multivariate tests performed to explore the association of tumour protein levels of Ki67 and DLX2 with time to death and metastasis. RESULTS: Univariate analysis demonstrated Ki67 as predictive of CaP-specific survival (DSS; P=0.022), and both Ki67 (P=0.025) and DLX2 (P=0.001) as predictive of future metastases. Multivariate analysis demonstrated Ki67 as independent of PSA, Gleason score and D'Amico risk category for DSS (HR=2.436, P=0.029) and both Ki67 (HR=3.296, P=0.023) and DLX2 (HR=3.051, P=0.003) as independent for future metastases. CONCLUSIONS: High Ki67 expression is only present in 6.8% of CaP patients and is predictive of reduced survival and increased risk of metastasis, independent of PSA, Gleason score and D'Amico risk category. DLX2 is a novel marker of increased metastasis risk found in 73% patients and 8.2% showed co-expression with a high Ki67 score. Two cancer cell proliferation markers, Ki67 and DLX2, may be able to inform clinical decision-making when identifying patients for active surveillance.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

MicroRNA in prostate cancer: functional importance and potential as circulating biomarkers.

BACKGROUND: This non-systematic review article aims to summarise the progress made in understanding the functional consequences of microRNA (miRNA) dysregulation in prostate cancer development, and the identification of potential miRNA targets as serum biomarkers for diagnosis or disease stratification. RESULTS: A number of miRNAs have been shown to influence key cellular processes involved in prostate tumourigenesis, including apoptosis-avoidance, cell proliferation and migration and the androgen signalling pathway. An overlapping group of miRNAs have shown differential expression in the serum of patients with prostate cancer of varying stages compared with unaffected individuals. The majority of studies thus far however, involve small numbers of patients and have shown variable and occasionally conflicting results CONCLUSION: MiRNAs show promise as potential circulating biomarkers in prostate cancer, but larger prospective studies are required to validate particular targets and better define their clinical utility.

Update on the management of T1 renal cortical tumours.

There are a range of treatment strategies for the management of patients with small incidental renal cortical tumours including active surveillance, radiofrequency ablation, cryotherapy, radical nephrectomy and partial nephrectomy. A large number of such tumours are benign and might therefore be over-treated with radical nephrectomy. There are emergent short-term oncological and clinical outcomes for cryotherapy and radiofrequency ablation, and recent studies have illustrated the benefits of partial nephrectomy for minimizing the risk of progression to chronic kidney disease. The outcomes of these different treatment methods are discussed.

Mammalian target of rapamycin: a new target in prostate cancer.

Molecular targets in prostate cancer are continually being explored, especially in the poor-prognosis androgen-independent phase of the disease, for which there are currently few therapeutic options. One such target is the mammalian target of rapamycin (mTOR) protein. Activation of mTOR results in sequential activation of downstream molecules, which ultimately results in cell division. In this review, we consider the rationale for pursuing mTOR as a therapeutic target in prostate cancer and summarize preclinical and clinical studies of mTOR inhibition in prostate cancer.

Resveratrol--a prostate cancer chemopreventive agent?

The incidence of prostate cancer in Western countries continues to rise. Whilst opinion remains divided on the best treatment for localized disease, intervention for metastatic, hormone-independent cancer remains extremely limited. The concept of chemoprevention is gaining popularity as an effective means of reducing the burden of prostate cancer on the population, and many compounds with putative chemopreventive activity are currently under investigation. Resveratrol is a plant-derived polyphenolic compound which has a wide spectrum of biological activity. It has anti-oxidant and anti-inflammatory properties, and may induce apoptosis as well as modulate the function of the androgen receptor in prostate cancer cell lines. Further studies to evaluate the use of this compound as a chemopreventive agent in prostate cancer are warranted.