Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XIST cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XIST breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis. These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XIST tumor cells in the brain. .

Glioblastoma (GBM) is the most common and aggressive malignant glioma, treatment of which has not improved significantly in many years. This is due to the unique challenges that GBM tumors present when designing and implementing therapies. Recently, immunotherapy in the form of immune checkpoint inhibition (ICI) has revolutionized the treatment of various malignancies. The application of immune checkpoint inhibition in GBM treatment has shown promising preclinical results. Unfortunately, this has met with little to no success in the clinic thus far. In this review, we will discuss the challenges presented by GBM tumors that likely limit the effect of ICI and discuss the approaches being tested to overcome these challenges.

Cytomegalovirus (CMV) is an important pathogen after allogeneic transplantation. However, few studies have examined CMV reactivation after autologous peripheral blood stem cell transplantation (APBSCT) to treat multiple myeloma (MM), especially in the setting of the newer chemotherapeutic agents and/or 2 sequential APBSCTs (ie, tandem transplantation). A retrospective chart review of patients with MM who underwent either single APBSCTor tandem transplantation was conducted to evaluate the incidence, risk factors, and outcomes of CMV infection at a single institution. A total of 104 patients with MM underwent transplantation during the study period, including 66 patients who received tandem transplantation. The majority of patients (66 of 104; 63.5%) were CMV-seropositive, and CMV viremia was frequently detected in this subgroup (32 of 66; 48.5%). No primary CMV infections were identified. CMV reactivation was more common in recipients of tandem transplantation than in recipients of single APBSCT (P \.001). In addition, patients who developed CMV viremia were more likely to have received conditioning therapy with melphalan, bortezomib, dexamethasone, and thalidomide compared with those without CMV reactivation (P 5 .015). However, on multiple logistic regression analysis, only receipt of tandem transplantation was significantly associated with CMV reactivation (odds ratio, 5.112; 95% confidence interval, 1.27-20.60; P 5 .022). Febrile episodes of CMV viremia were observed in 17 patients (17 of 32; 53.1%), and invasive CMV disease was diagnosed in 1 patient. Our data suggest that CMV reactivation after APBSCT for MM is relatively common, and that viremia is often associated with fever. CMV surveillance should be considered, especially when tandem transplantation is performed using combination chemotherapy with high-dose melphalan.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.