Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression.

MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer and resulting in increased tumor growth and metastasis. Here we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanoliposomes resulted in increased tumor growth and metastasis, and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line-based overexpression of sense or antisense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer.

Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.

Adrenergic stimulation adversely affects tumor growth and metastasis, but the underlying mechanisms are not well understood. Here, we uncovered a novel mechanism by which catecholamines induce inflammation by increasing prostaglandin E2 (PGE2) levels in ovarian cancer cells. Metabolic changes in tumors isolated from patients with depression and mice subjected to restraint stress showed elevated PGE2 levels. Increased metabolites, PTGS2 and PTGES protein levels were found in Skov3-ip1 and HeyA8 cells treated with norepinephrine (NE), and these changes were shown to be mediated by ADRB2 receptor signaling. Silencing PTGS2 resulted in significantly decreased migration and invasion in ovarian cancer cells in the presence of NE and decreased tumor burden and metastasis in restraint stress orthotopic models. In human ovarian cancer samples, concurrent increased ADRB2, PTGS2 and PTGES expression was associated with reduced overall and progression-free patient survival. In conclusion, increased adrenergic stimulation results in increased PGE2 synthesis via ADRB2-Nf-kB-PTGS2 axis, which drives tumor growth and metastasis.

A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy.

OBJECTIVE: To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy. METHODS: A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five-year OS. RESULTS: 312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19-85); 86% women had advanced stage (III-IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR=0.98, 95% CI 0.97-1.00, p=0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five-year OS was constructed and internally validated (bootstrap-corrected concordance index=0.737). CONCLUSION: Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed.