No abstract

ClinicalTrials.gov identifier: NCT02388919.

Context Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer (OvCa) have produced conflicting results. Objective To determine the relationships between BRCA1/2 deficiency (i.e., mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole exome mutation rate in OvCa. Design, Setting, and Patients Observational study of multidimensional genomics and clinical data on 316 high-grade serous OvCa cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project. Main Outcome Measures OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome). Results BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16–0.69, P=0.003; 5-year OS: 61% for BRCA2 mutated vs. 25% for BRCA wild-type [wt] cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22–0.74, P=0.004; 3-year PFS: 44% for BRCA2 mutated vs. 16% for BRCA wt cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) were associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2 mutated vs. 82% [P=0.02] and 80% [P=0.05] for BRCA wt and BRCA1 mutated cases, respectively) and longer platinum-free duration (median platinum-free duration: 18.0 months for BRCA2 mutated vs. 11.7 [P=0.02] and 12.5 [P=0.04] months for BRCA wt and BRCA1 mutated cases, respectively). Further investigation revealed that BRCA2 mutated, but not BRCA1 mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wt cases across the whole exome (median mutation number per sample: 84 for BRCA2 mutated vs. 52 for BRCA wt cases, false-discovery rate <0.1). Conclusions BRCA2 mutation, but not BRCA1 deficiency, is associated with improved survival, chemotherapy response, and genome instability compared with BRCA wild-type.

Merging tumor targeting and molecular-genetic imaging into an integrated platform is limited by lack of strategies to enable systemic yet ligand-directed delivery and imaging of specific transgenes. Many eukaryotic viruses serve for transgene delivery but require elimination of native tropism for mammalian cells; in contrast, prokaryotic viruses can be adapted to bind to mammalian receptors but are otherwise poor vehicles. Here we introduce a system containing cis-elements from adeno-associated virus (AAV) and single-stranded bacteriophage. Our AAV/phage (AAVP) prototype targets an integrin. We show that AAVP provides superior tumor transduction over phage and that incorporation of inverted terminal repeats is associated with improved fate of the delivered transgene. Moreover, we show that the temporal dynamics and spatial heterogeneity of gene expression mediated by targeted AAVP can be monitored by positron emission tomography. This new class of targeted hybrid viral particles will enable a wide range of applications in biology and medicine.

Summary Integrated genomic analyses revealed a miRNA-regulatory network, which further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141 and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition (EMT) by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth.