Some tumor suppressing miRNAs target multiple oncogenes concurrently and therefore may be useful as cancer therapeutic agents. Further, such miRNAs may be useful to address chemotherapeutic resistance in cancer, which remains a primary clinical challenge in need of solutions. Thus, cytoprotective processes upregulated in cancer cells that are resistant to chemotherapy are a logical target for investigation. Here we report that overexpression of miR-634 activates the mitochondrial apoptotic pathway by direct concurrent targeting of genes associated with mitochondrial homeostasis, anti-apoptosis, antioxidant ability and autophagy. In particular, we show how enforced expression of miR-634 enhanced chemotherapy-induced cytotoxicity in a model of esophageal squamous cell carcinoma (ESCC), where resistance to chemotherpy remains clinically problematic. Our findings illustrate how reversing miR-634-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy.

Pancreatic cancer is characterized by extensive stromal desmoplasia which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity – cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin (Dox) penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active versus passive drug diffusion). For both types, the pHIFU exposures which were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized Dox concentration by up to 4.5 fold compared to controls. Furthermore, normalized Dox concentration was associated with the cavitation metrics (p < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, i.e., Dox infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors

Treatment can pose a daunting challenge for young women with body-image issues, and reawaken a previous problem.

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacological inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared to Stat3-sufficient control tumors, Stat3-/- cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes post-chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3-/- cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3-/- cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3-/- and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.

Long noncoding RNAs (lncRNAs) have emerged as essential players in cancer biology. Using recent large-scale RNA-seq datasets, especially those from The Cancer Genome Atlas (TCGA), we have developed “The Atlas of Noncoding RNAs in Cancer” (TANRIC, http://bioinformatics.mdanderson.org/main/TANRIC:Overview), a user-friendly, open-access web resource for interactive exploration of lncRNAs in cancer. It characterizes the expression profiles of lncRNAs in large patient cohorts of 20 cancer types, including TCGA and independent data sets (>8,000 samples overall). TANRIC enables researchers to rapidly and intuitively analyze lncRNAs of interest (annotated lncRNAs or any user-defined ones) in the context of clinical and other molecular data, both within and across tumor types. Using TANRIC, we have identified a large number of lncRNAs with potential biomedical significance, many of which show strong correlations with established therapeutic targets and biomarkers across tumor types or with drug sensitivity across cell lines. TANRIC represents a valuable tool for investigating the function and clinical relevance of lncRNAs in cancer, greatly facilitating lncRNA-related biological discoveries and clinical applications.