Glioblastoma is the most common and lethal primary brain malignancy. Despite major investments in research into glioblastoma biology and drug development, treatment remains limited and survival has not substantially improved beyond 1–2 years. Cancer stem cells (CSC) or glioma stem cells (GSC) refer to a population of tumor originating cells capable of self-renewal and differentiation. While controversial and challenging to study, evidence suggests that GCSs may result in glioblastoma tumor recurrence and resistance to treatment. Multiple treatment strategies have been suggested at targeting GCSs, including immunotherapy, posttranscriptional regulation, modulation of the tumor microenvironment, and epigenetic modulation. In this review, we discuss recent advances in glioblastoma treatment specifically focused on targeting of GCSs as well as their potential integration into current clinical pathways and trials.

Background Human cytomegalovirus (HCMV) is an oncomodulatory human herpesvirus that has been detected in glioblastoma (GBM) and is associated with worse prognosis in patients with the disease. The effects of HCMV systemic infection on survival in GBM patients, however, are largely unknown. We aimed to determine the association between HCMV serostatus at diagnosis and survival via a retrospective cohort study of GBM patients. Methods Plasma from 188 GBM patients treated at the Ben and Catherine Ivy Center (Seattle, WA) was tested for HCMV serostatus via enzyme-linked immunosorbent assays of anti-HCMV immunoglobulin (Ig)G. HCMV IgG serostatus was analyzed with respect to each patient’s progression-free and overall survival (OS) via log-rank and multivariable Cox regression analysis. Results Ninety-seven of 188 (52%) patients were anti-HCMV IgG seropositive. Median OS was decreased in the IgG+ cohort (404 days) compared to IgG− patients (530 days; P = .0271). Among O6-methylguanine-DNA methyltransferase (MGMT) unmethylated patients (n = 96), median OS was significantly decreased in IgG+ patients (336 days) compared to IgG− patients (510 days; P = .0094). MGMT methylation was associated with improved OS in IgG+ patients versus those who were unmethylated (680 vs 336 days; P = .0096), whereas no such association was observed among IgG− patients. Conclusions In this study, HCMV seropositivity was significantly associated with poorer OS in GBM patients. This finding suggests prior infection with HCMV may play an important role in GBM patient outcomes, and anti-HCMV antibodies may, therefore, prove a valuable prognostic tool in the management of GBM patients.

Background Immunocompetent animal models are required to study tumor-host interactions, immunotherapy, and immunotherapeutic combinations, however the currently available immunocompetent lung cancer models have substantial limitations. While orthotopic models potentially help fill this gap, the utility of these models has been limited by the very small number of murine lung cancer cell lines capable of forming orthotopic tumors in immunocompetent C57BL/6 hosts. Methods Primary lung tumors with specific genetic alterations were created in C57BL/6 background mice. These tumors were then passaged through other animals to increase tumorigenicity and select for the ability to grow in a non-self animal. Once tumors demonstrated growth in a non-self host, cell lines were established. Successful cell lines were evaluated for the ability to produce orthotopic lung tumors in immunocompetent hosts. Results We produced six murine lung cancer lines capable of orthotopic lung tumor formation in immunocompetent C57BL/6 animals. These lines demonstrate the expected genetic alterations based on their primary tumor genetics. Conclusions These novel cell lines will be useful for evaluating tumor-host interactions, the impact of specific oncogenic alterations on the tumor microenvironment, and immunotherapeutic approaches. This method of generating murine lines capable of orthotopic growth can likely be applied to other tumors and will broaden the applicability of pre-clinical testing of immunotherapeutic treatment regimens.