Construction of IL-13 Receptor α2-Targeting Resveratrol Nanoparticles against Glioblastoma Cells: Therapeutic Efficacy and Molecular Effects

Glioblastoma multiforme (GBM) is the most common lethal primary brain malignancy without reliable therapeutic drugs. IL-13Rα2 is frequently expressed in GBMs as a molecular marker. Resveratrol (Res) effectively inhibits GBM cell growth but has not been applied in vivo because of its low brain bioavailability when administered systemically. A sustained-release and GBM-targeting resveratrol form may overcome this therapeutic dilemma. To achieve this goal, encapsulated Res 30 ± 4.8 nm IL-13Rα2-targeting nanoparticles (Pep-PP@Res) were constructed. Ultraviolet spectrophotometry revealed prolonged Res release (about 25%) from Pep-PP@Res in 48 h and fluorescent confocal microscopy showed the prolonged intracellular Res retention time of Pep-PP@Res (>24 h) in comparison with that of free Res (<4 h) and PP@Res (<4 h). MTT and EdU cell proliferation assays showed stronger suppressive effects of Pep-PP@Res on rat C6 GBM cells than that of PP@Res (p = 0.024) and Res (p = 0.009) when used twice for 4 h/day. Pep-PP@Res had little toxic effect on normal rat brain cells. The in vivo anti-glioblastoma effects of Res can be distinctly improved in the form of Pep-PP@Res nanoparticles via activating JNK signaling, upregulating proapoptosis gene expression and, finally, resulting in extensive apoptosis. Pep-PP@Res with sustained release and GBM-targeting properties would be suitable for in vivo management of GBMs.

Association between height and the risk of primary brain malignancy in adults: A nationwide population-based cohort study

Purpose The association between height and the risk of developing primary brain malignancy remains unclear. We evaluated the association between height and risk of primary brain malignancy based on a nationwide population-based database of Koreans. Methods Using data from the Korean National Health Insurance System cohort, 6,833,744 people over 20 years of age that underwent regular national health examination were followed from January 2009 until the end of 2017. We documented 4,771 cases of primary brain malignancy based on an ICD-10 code of C71 during the median follow-up period of 7.30 years and 49,877,983 person-years. Results When dividing the population into quartiles of height for each age group and sex, people within the highest height quartile had a significantly higher risk of brain malignancy, compared to those within the lowest height quartile (HR 1.21 CI 1.18–1.32) after adjusting for potential confounders. We also found that the risk of primary brain malignancy increased in proportion with the quartile increase in height. After analyzing subgroups based on older age (≥ 65) and sex, we found positive relationships between height and primary brain malignancy in all subgroups. Conclusions This study is the first to suggest that height is associated with increased risk of primary brain malignancy in the East-Asian population. Further prospective and larger studies with precise designs are needed to validate our findings.

Clinical outcomes in patients with malignant brain tumors admitted to the ICU.

e14034 Background: Primary brain malignancy is distinct from other oncologic diagnoses in its presentation and course. Recent treatment advances have modestly improved survival; yet, prognoses for afflicted patients remain grim, which often leads to non-oncology providers questioning the pertinence of aggressive critical care in this population. By relating patient and disease factors with mortality rates in malignant brain tumor (MBT) patients admitted for critical care, we seek to identify valuable prognostic factors and clarify the expected outcomes following intensive care unit (ICU) admission among these patients. Methods: A single-institution retrospective review was performed of 80 primary MBT patients admitted to neuro- or medical ICUs over a five-year period. The Electronic Health Record (EHR) was queried to identify MBT patients who had been admitted to the ICU. Patients undergoing planned surgical resection or with post-operative complications were excluded, as were patients with brain metastases. A matched control group of 80 solid tumor (ST) patients (excluding brain tumors) was included for comparison. Similar aged matched controls were randomly identified via EHR over the same time period to include non-brain, ST patients admitted to the ICU. Demographic, oncologic, and admission data were related to outcomes, which included complication rates (ICU mortality, six-month mortality) and change in Karnofsky Performance Status (KPS) score. Results: The average age was 55.9 (20-83) and 62.8 (27-89) years in the MBT and ST group, respectively (p = 0.10). ICU mortality was 15% and 21% (p = 0.411) and six-month mortality was 46% and 65% (p = 0.10) in the MBT and control groups, respectively. The most common reasons for ICU admission were seizures (36%) and septic shock (21%) among MBT patients, compared to hypoxic respiratory failure (43%) and septic shock (30%) among ST patients. The MBT group’s KPS score decreased by 23.6 ± 26.82 during their ICU admission, while the control group KPS decreased by 27.0 ± 28.3 (p = 0.87). Average length of ICU stay was 3.82 ± 4.4 days in the MBT group, compared to 2.95 ± 1.83 days in the control ST group (p = 0.29). Average length of hospital stay was 9.07 ± 9.0 days in the MBT group and 8.67 ± 7.76 days in the ST group (p = 0.92). Conclusions: No significant difference was observed in ICU or 6-month mortality when comparing primary MBT and ST patients. Change in KPS score across ICU admissions was similar among the two groups. Our data indicate that despite their guarded prognosis, MBT patients fare no worse than those with other solid tumor types at our institution in the critical care setting. These similarities in mortality and functional scores justify medical ICU admission in patients with primary brain malignancy, and should inform intensivist and oncologist admission patterns.

Glioma Stem Cells as Immunotherapeutic Targets: Advancements and Challenges

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.

Exosomes in Gliomas: Biogenesis, Isolation, and Preliminary Applications in Nanomedicine

Exosomes are phospholipid-based particles endogenously produced by both normal and tumor cells. Initially identified as a pathway for shuttling cellular waste, for a long time they were thought to act as “garbage bags”, and only in the past few years have they emerged as a promising drug delivery system. In this review, we provide an overview of the knowledge about exosome architecture and biogenesis and the recent progress in isolation methods. Furthermore, we describe the mechanisms involved in both extra- and intracellular communication with a focus on glioma brain tumors. Glioma is considered a rare disease and is the most prominent aggressive brain malignancy. How exosomes target glial tumoral cells in vivo remains largely unknown. However, they are able to influence numerous physio-pathological aspects. Here, we discuss the role they play in this heterogeneous and complex microenvironment and their potential applications.

LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population During Temozolomide Therapy in Glioblastoma

ABSTRACTGlioblastoma (GBM) is the most common primary brain malignancy in adults, with a 100% recurrence rate and a 21-month median survival. Our lab and others have shown that GBM contains a subpopulation of glioma stem cells (GSCs) that expand with chemotherapy, and that may contribute to therapeutic resistance and recurrence in GBM. To investigate the mechanism behind this expansion, we applied gene set expression analysis (GSEA) to patient-derived xenograft (PDX) cells in response to temozolomide (TMZ), the most commonly used chemotherapy against GBM. Results showed significant enrichment of cancer stem cell and cell cycle pathways (FDR<0.25). The ligand of numb protein 1 (LNX1), a known regulator of Notch signaling by targeting negative regulator Numb, is strongly upregulated after TMZ therapy (p<0.0001) and is negatively correlated with survival of GBM patients. LNX1 is also upregulated after TMZ therapy in multiple PDX lines with concomitant downregulations in Numb and upregulations in intracellular Notch1 (NICD). Overexpression of LNX1 results in Notch1 signaling activation and increased CSC populations. In contrast, knocking down LNX1 reverses these changes, causing a significant downregulation of NICD, eliminating induction of functional stemness after TMZ therapy, and resulting in more prolonged median survival in a mouse model. Our data indicate that removing LNX1 activity results in a less aggressive and more chemo-sensitive tumor. Based on this, we propose that during anti-GBM chemotherapy, LNX1-regulated Notch1 signaling promotes stemness and contributes to therapeutic resistance.

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

Glioblastoma Multiforme is a highly aggressive brain malignancy commonly refractory to classical and novel chemo-, radio- and immuno-therapies, with median survival times of ~15 months following diagnosis. Poor immunological responses exemplified by the down-regulation of T-cell activity, and upregulation of immunosuppressive cells within the tumour micro-environment have limited the effectiveness of immunotherapy in GBM to date. Here we show that GBM cells express a large repertoire of inhibitory checkpoint ligands. Furthermore, GBM cells with an enhanced stem cell-like phenotype exhibit heightened levels of inhibitory checkpoint ligands, compared to non-stem cell-like GBM cells. Understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion are necessary to develop effective immuno-therapeutics.