The biological role of steroid 5a-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (nZ62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (PZ0.02), higher cancer stage (PZ0.01), and higher serum prostate specific antigen (PSA) levels (PZ0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (PZ0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor b 1 (TGFB1), endothelin (EDN1), TGFa (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 mM). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors.

Background Gastric cancer is a leading cause of cancerrelated mortality, and chemotherapeutic options are currently limited. PIM1 kinase, an oncogene that promotes tumorigenesis in several cancer types, might represent a novel therapeutic target in gastric cancer. Methods We studied the expression and genomic status of PIM1 in human primary gastric normal and tumor tissue samples by immunohistochemistry and array-based comparative genomic hybridization (aCGH). To ascertain whether PIM1 expression predicted susceptibility to PIM1 kinase-specific inhibition, the cytotoxic effect of a previously reported PIM1-specific small molecular inhibitor (K00135) was investigated in two gastric cancer cell lines with high (IM95) and undetectable (NUGC-4) PIM1 expression levels. Results PIM1 expression was exclusively nuclear in normal gastric epithelial cells, while aberrant expression/ localization (decreased nuclear and/or increased cytoplasmic expression) was observed in 75.6% (68/90) of the human gastric cancer tissue samples, with a significant inverse correlation between nuclear and cytoplasmic expression levels. Clinicopathological analyses revealed that decreased nuclear PIM1 expression correlated with poorer survival and greater depth of tumor invasion, while increased cytoplasmic PIM1 expression correlated inversely with the presence of lymphovascular invasion. Highlevel PIM1 amplification was identified in 10.5% of gastric cancers by aCGH. K00135 impaired the survival of IM95, while it had no significant effect on NUGC-4 survival. Conclusion Our findings demonstrate the clinical and therapeutic relevance of PIM1 in gastric cancers, and suggest that PIM1 represents a potential therapeutic target.

The value of precision oncology initiatives in Asian contexts remains unresolved. Here, we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays, such as immunohistochemistry, copy number analysis and in situ hybridization tests, were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5-4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1-68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks.

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