Outcome Of Glioblastoma Patients Research Articles

Phenotypic plasticity of myeloid cells in glioblastoma development, progression, and therapeutics.

Glioblastoma (GBM) is the most common and malignant type of intracranial tumors with poor prognosis. Accumulating evidence suggests that phenotypic alterations of infiltrating myeloid cells in the tumor microenvironment are important for GBM progression. Conventional tumor immunotherapy commonly targets T-cells, while innate immunity as a therapeutic target is an emerging field. Targeting infiltrating myeloid cells that induce immune suppression in the TME provides a novel direction to improve the prognosis of patients with GBM. The factors released by tumor cells recruit myeloid cells into tumor bed and reprogram infiltrating myeloid cells into immunostimulatory/immunosuppressive phenotypes. Reciprocally, infiltrating myeloid cells, especially microglia/macrophages, regulate GBM progression and affect therapeutic efficacy. Herein, we revisited biological characteristics and functions of infiltrating myeloid cells and discussed the recent advances in immunotherapies targeting infiltrating myeloid cells in GBM. With an evolving understanding of the complex interactions between infiltrating myeloid cells and tumor cells in the tumor microenvironment, we will expand novel immunotherapeutic regimens targeting infiltrating myeloid cells in GBM treatment and improve the outcomes of GBM patients.

Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma.

Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyper-aggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. Syngeneic GBM models and GBM patient specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide clear evidence that diet modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.

The Prognostic Effect of Dexamethasone on Patients With Glioblastoma: A Systematic Review and Meta-Analysis.

Background: Dexamethasone (DEX) is widely adopted to reduce tumor-associated edema in glioblastoma (GBM) patients despite its side effects. However, the benefits of using DEX in GBM patients remains elusive.Methods: In this study, we performed a comprehensive meta-analysis to address this concern. We searched the relevant studies from PubMed, Web of Science, and EMBASE databases, and then applied random or fixed-effects models to generate estimated summary hazard radios (HRs) and the 95% confidence intervals (CIs). Moreover, subgroup and sensitivity analysis were conducted and publication bias were further evaluated.Results: Ten articles with a total of 2,230 GBM patients were eligible according to the inclusion criteria. In the assessment of overall survival (OS), meta-analysis data revealed that DEX was significantly associated with the poor prognosis of GBM patients (HR=1.44, 95% CI=1.32−1.57). In the progression-free survival (PFS), the pooled results indicated that the use of DEX can increase 48% death risk for GBM patients (HR=1.48, 95% CI=1.11−1.98). Subgroup analyses revealed that DEX was associated with poorer outcome of GBM in subgroup of newly diagnosed patients and GBM patients treated with ≥ 2mg/day. Sensitivity analyses showed that no study changed the pooled results materially for both OS and PFS analyses. The funnel plot had no obvious asymmetry.Conclusion: Our findings partly confirmed that use of DEX was associated with poor treatment outcome in GBM patients. To reach a definitive conclusion, large samples from multi-centers are urgent to address this concern.

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells.

Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.

Abstract IA-006: Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors

Abstract PARP inhibitors (PARPi) enhance radiation sensitivity in multiple cancer models, both in vitro and in vivo. Our observation that the radiosensitizing properties of PARPi are most pronounced in rapidly proliferating cells is reflected in early phase clinical trial data showing exacerbation of acute radiation toxicity in rapidly proliferating tissues such as oropharyngeal and esophageal mucosa. Lack of radiosensitization in late responding, slowly proliferating normal tissues indicates that PARPi may be more effectively combined with radiation therapy (RT) in patients with brain tumors. We are therefore evaluating the oral PARPi olaparib in combination with RT and/or temozolomide (TMZ) in the treatment of glioblastoma (GBM), the most prevalent and most aggressive primary brain tumor. Patients with GBM experience very poor outcomes in terms of median survival (c.1 year) and neurocognitive decline caused primarily by RT. Olaparib was initially evaluated in combination with daily low-dose TMZ in patients with recurrent GBM in the OPARATIC trial. Pharmacokinetic studies revealed that olaparib penetrates both core and margin regions of GBM, indicating that the BBB is significantly disrupted throughout these tumors. Olaparib could be safely combined with daily TMZ (75 mg/m2), but intermittent olaparib dosing (150 mg three days per week) was required to avoid dose-limiting hematological toxicity. Early phase testing of the olaparib-radiotherapy combination is now underway in three populations of patients with newly diagnosed GBM. Patients aged >65 with MGMT unmethylated GBM are being recruited to a randomized, placebo-controlled phase II study (PARADIGM) after a phase I dose escalation study showed that olaparib (200 mg twice daily) was extremely well tolerated when combined with brain irradiation (40 Gray in 15#). Good performance status patients aged <70 are being recruited to two parallel phase I dose escalation studies: patients with MGMT unmethylated tumors are receiving daily olaparib with RT (60 Gy in 30#) without TMZ, while patients with MGMT methylated tumors are receiving intermittent olaparib with standard chemoradiation (60 Gy). The impact of PARPi on RT induced neurotoxicity is being investigated in preclinical studies. In vitro data show that PARPi reduce proliferation of neural stem cells and protect them against RT induced apoptosis, while in vivo studies support the emerging concept that RT induced neuroinflammation is important in the pathogenesis of neurotoxicity. Importantly, preliminary PET and immunohistochemical studies have shown robust anti-neuroinflammatory effects of PARPi in this context. Ongoing experiments are defining the roles of microglia, astrocytes and neurogenesis in this phenomenon. These diverse data sets provide support for our hypothesis that combining PARPi with RT has potential to improve outcomes for GBM patients by enhancing tumor control while simultaneously suppressing neuroinflammation and alleviating RT related neurocognitive decline. Citation Format: Anthony J. Chalmers, Rodrigo Gutierrez-Quintana, David J. Walker, Karin Williams, Duncan Forster, Mark R. Jackson, Sarah Derby, Jon Stobo, Lorna Sweeting, Caroline Kelly, Stephen Durant, Kaye J. Williams. Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-006.

13109 Phosphorylation state of Myristoylated Alanine-Rich C-Kinase Substrate Effector Domain mimetics determines its cytotoxicity in glioblastoma and macrophage model

ABSTRACT IMPACT: This study provides insight into how MED2 impacts the immune cells surrounding glioblastoma that help it to grow and spread; having a more complete understanding of how MED2 works will help us better develop therapies that may one day enter the clinic to improve patient outcomes in glioblastoma. OBJECTIVES/GOALS: The purpose of this study was to determine whether the phosphorylation state of the MED2 peptide impacts its biological activity in GBM and macrophages. MED2 variants include the phosphorylatable wild-type (MED2), pseudo-phosphorylated (MED2-PP), non-phosphorylatable (MED2-NP) and control length (CTL2) peptides. METHODS/STUDY POPULATION: MED2, MED2-NP, MED2-PP, and CTL2 were screened against a panel of molecularly characterized glioblastoma patient derived xenografts and IL4/13 stimulated M2-like THP-1 macrophages. The luminescent cell viability assay, CellTiter-Glo, was used to determine viability. RESULTS/ANTICIPATED RESULTS: The proneural lines XD456 and X1441 were highly sensitive to 5 µM MED2 and 5 µM MED2NP compared to 5 µM MED2PP (p<0.001). There was no statistically significant difference between untreated, 5 µM CTL2, and 5 µM MED2PP groups or between the MED2NP and MED2 treated groups. M2-like THP-1 macrophages were highly sensitive to 10 µM MED2NP compared to 10 µM CTL2 (p<0.01) and 10 µM MED2PP (p<0.01) No statistically significant difference was observed between untreated, 10 µM MED2, 10 µM MED2PP, and 10 µM CTL2 groups. DISCUSSION/SIGNIFICANCE OF FINDINGS: The phosphorylation state of MED2 determines its toxicity. When MED2 is phosphorylated, it is nontoxic to GBM or M2-like macrophages. The non-phosphorylatable version is toxic to both GBM and M2-like macrophages. The wild-type peptide is toxic to GBM but not M2-like macrophages, suggesting that MED2 may be phosphorylated in M2-like macrophages.

Impact of Body Mass Index on Survival Outcome in Patients with Newly Diagnosed Glioblastoma: A Retrospective Single-Center Study.

Introduction:The impact of obesity on survival outcomes in patients with glioblastoma (GBM) has not been well reported and the results for patients are currently unclear. We investigated the effect of obesity on survival outcomes in patients with newly diagnosed GBM.Methods:Using electronic medical records, all GBM patients that visited the Seoul St. Mary’s Hospital between 2008 and 2018 were reviewed. A total of 177 patients met our eligibility criteria. The cut-off point for BMI was 23.0 kg/m2 based on previous studies which focused on Asian populations.Results:A total of 177 patients met our eligibility criteria. The overall median BMI of patients was 24.5 kg/m2 (range 15.82-39.26). About 62 patients who had a BMI less than the cut-off value were assigned to the “lower BMI” group, while 115 patients who had a BMI greater than the cut-off value were assigned to the “higher BMI” group. In Kaplan-Meier survival analysis, the median OS of the higher BMI group was longer than that of the lower BMI group (21.3 months vs 15.3 months, P = .002). In multivariate Cox regression analysis for OS, lower BMI was associated with inferior OS (HR 1.48 CI 1.06-2.08, P = .002).Conclusion:Our findings suggest that elevated BMI may be associated with better survival in patients with newly diagnosed GBM. Additional larger prospective studies could help validate our findings to confirm the effect of body composition and survival outcomes in GBM patients.

Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study.

BackgroundChronotherapy is an innovative approach to improving survival through timed delivery of anti-cancer treatments according to patient daily rhythms. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for glioblastoma (GBM). Whether timing of TMZ administration affects GBM patient outcome has not previously been studied. We sought to evaluate maintenance TMZ chronotherapy on GBM patient survival.MethodsThis retrospective study reviewed patients with newly diagnosed GBM from January 1, 2010 to December 31, 2018 at Washington University School of Medicine who had surgery, chemoradiation, and were prescribed TMZ to be taken in the morning or evening. The Kaplan–Meier method and Cox regression model were used for overall survival (OS) analyses. The propensity score method accounted for potential observational study biases. The restricted mean survival time (RMST) method was performed where the proportional hazard assumption was violated.ResultsWe analyzed 166 eligible GBM patients with a median follow-up of 5.07 years. Patients taking morning TMZ exhibited longer OS compared to evening (median OS, 95% confidence interval [CI] = 1.43, 1.12–1.92 vs 1.13, 0.84–1.58 years) with a significant year 1 RMST difference (−0.09, 95% CI: −0.16 to −0.018). Among MGMT-methylated patients, median OS was 6 months longer for AM patients with significant RMST differences at years 1 (−0.13, 95% CI = −0.24 to −0.019) to 2.5 (−0.43, 95% CI = −0.84 to −0.028). Superiority of morning TMZ at years 1, 2, and 5 (all P < .05) among all patients was supported by RMST difference regression after adjusting for confounders.ConclusionsOur study presents preliminary evidence for the benefit of TMZ chronotherapy to GBM patient survival. This impact is more pronounced in MGMT-methylated patients.

Correlation of genetic alterations by whole-exome sequencing with clinical outcomes of glioblastoma patients from the Lebanese population.

IntroductionGlioblastoma (GBM) is an aggressive brain tumor associated with high degree of resistance to treatment. Given its heterogeneity, it is important to understand the molecular landscape of this tumor for the development of more effective therapies. Because of the different genetic profiles of patients with GBM, we sought to identify genetic variants in Lebanese patients with GBM (LEB-GBM) and compare our findings to those in the Cancer Genome Atlas (TCGA).MethodsWe performed whole exome sequencing (WES) to identify somatic variants in a cohort of 60 patient-derived GBM samples. We focused our analysis on 50 commonly mutated GBM candidate genes and compared mutation signatures between our population and publicly available GBM data from TCGA. We also cross-tabulated biological covariates to assess for associations with overall survival, time to recurrence and follow-up duration.ResultsWe included 60 patient-derived GBM samples from 37 males and 23 females, with age ranging from 3 to 80 years (mean and median age at diagnosis were 51 and 56, respectively). Recurrent tumor formation was present in 94.8% of patients (n = 55/58). After filtering, we identified 360 somatic variants from 60 GBM patient samples. After filtering, we identified 360 somatic variants from 60 GBM patient samples. Most frequently mutated genes in our samples included ATRX, PCDHX11, PTEN, TP53, NF1, EGFR, PIK3CA, and SCN9A. Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). EGFR and NF1 mutations were associated with the frontal lobe and temporal lobe in our LEB-GBM cohort, respectively.ConclusionsOur WES analysis confirmed the similarity in mutation signature of the LEB-GBM population with TCGA cohorts. It showed that 1 out of the 50 commonly GBM candidate gene mutations is associated with decreased overall survival among the Lebanese cohort. This study also highlights the need for studies with larger sample sizes to inform clinicians for better prognostication and management of Lebanese patients with GBM.

NCOG-26. IMPACT OF GENDER ON TUMOR TREATING FIELDS COMPLIANCE IN PATIENTS WITH GLIOBLASTOMA

Abstract BACKGROUND Tumor treating fields (TTFields) has emerged as a novel antimitotic modality to treat glioblastoma (GBM). Recently, a positive association was reported between TTFields dose at the tumor bed and survival outcomes in GBM patients. Dose density depends upon power density and compliance rate (cumulative amount of time TTFields therapy is delivered to the patient). Increased compliance with TTFields has been proposed as an independent prognostic factor for improved clinical benefits. There is evidence that females tend to respond better than males to standard therapy. However, the impact of gender and age on TTFields compliance is not fully understood in GBM patients. OBJECTIVE To investigate potential interactions amongst age, gender and TTFields compliance in GBM patients. METHODS A cohort of 16 patients (males =9; females=7; mean-age=60.8±7.6years) with newly diagnosed and recurrent GBM receiving TTFields were analyzed retrospectively. Device usage time was collected from internal log files in each case. The mean duration of TTFields therapy in patients was 4 months. Chi-square and independent sample T-tests were performed to evaluate differences in compliance rates based on patient age and gender and to examine gender-age relationships. Additionally, Pearson correlation analyses were performed to determine associations between gender and compliance rates. The probability (p) value of 0.05 was considered significant. RESULTS A trend (p=0.067) towards greater TTFields compliance was observed in females (80.1±0.11%) versus males (63.0±0.22%). Additionally, there was a strong positive correlation (R=0.73; p=0.058) between age and compliance rates for female patients. There were 6 patients ≥ 65 years and 10 patients &amp;lt; 65 years. However, we did not find significant differences in compliance rate and gender variables between patients ≥ 65 years and &amp;lt; 65 years of age. CONCLUSIONS Our results demonstrate gender influences TTFields compliance amongst GBM patients. However, future studies with larger cohorts are warranted to validate these findings.

Predicting Survival in Glioblastoma Patients Using Diffusion MR Imaging Metrics—A Systematic Review

Simple SummaryAn accurate survival analysis is crucial for disease management in glioblastoma (GBM) patients. Due to the ability of the diffusion MRI techniques of providing a quantitative assessment of GBM tumours, an ever-growing number of studies aimed at investigating the role of diffusion MRI metrics in survival prediction of GBM patients. Since the role of diffusion MRI in prediction and evaluation of survival outcomes has not been fully addressed and results are often controversial or unsatisfactory, we performed this systematic review in order to collect, summarize and evaluate all studies evaluating the role of diffusion MRI metrics in predicting survival in GBM patients. We found that quantitative diffusion MRI metrics provide useful information for predicting survival outcomes in GBM patients, mainly in combination with other clinical and multimodality imaging parameters.Despite advances in surgical and medical treatment of glioblastoma (GBM), the medium survival is about 15 months and varies significantly, with occasional longer survivors and individuals whose tumours show a significant response to therapy with respect to others. Diffusion MRI can provide a quantitative assessment of the intratumoral heterogeneity of GBM infiltration, which is of clinical significance for targeted surgery and therapy, and aimed at improving GBM patient survival. So, the aim of this systematic review is to assess the role of diffusion MRI metrics in predicting survival of patients with GBM. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic literature search was performed to identify original articles since 2010 that evaluated the association of diffusion MRI metrics with overall survival (OS) and progression-free survival (PFS). The quality of the included studies was evaluated using the QUIPS tool. A total of 52 articles were selected. The most examined metrics were associated with the standard Diffusion Weighted Imaging (DWI) (34 studies) and Diffusion Tensor Imaging (DTI) models (17 studies). Our findings showed that quantitative diffusion MRI metrics provide useful information for predicting survival outcomes in GBM patients, mainly in combination with other clinical and multimodality imaging parameters.

Glioblastoma cell differentiation trajectory predicts the immunotherapy response and overall survival of patients.

Glioblastoma (GBM) is the most common and lethal primary brain tumor. In this study, we aimed to investigate the differentiation states of GBM cells and their clinical relevance. Integrated single-cell RNA-sequencing (scRNA-seq) data and bulk RNA-seq data from GBM samples were used for analysis. Two subsets of GBM cells in distinct differentiation states were characterized, and 498 GBM cell differentiation-related genes (GDRGs) were identified. GDRGs were significantly correlated with immune regulation and metabolic pathways. We classified the GBM patients into two groups based on the expression of GDRGs in tumors and found that the cell differentiation-based classification successfully predicted patient overall survival (OS), immune checkpoint expression and likelihood of immunotherapy response in GBMs. FN1, APOE, RPL7A and GSTM2 were the 4 most significant survival-predicting GDRGs, and patients with different expression levels of each of these genes had distinct survival outcomes. Finally, a nomogram composed of the GDRG signature, age, pharmacotherapy, radiotherapy, IDH mutations and MGMT promoter methylation was generated and validated in two large GBM cohorts to predict GBM prognosis. This study highlights the significant roles of cell differentiation in predicting the clinical outcomes of GBM patients and their potential response to immunotherapy, suggesting promising therapeutic targets for GBM.

Association between temporal muscle thickness and clinical outcomes in patients with newly diagnosed glioblastoma.

Temporal muscle thickness (TMT) has been suggested as a novel biomarker that can represent sarcopenia in head and neck malignancies. This study investigated the association of TMT with clinical outcomes in patients with newly diagnosed glioblastoma (GBM). Using electronic medical records, all GBM patients between 2008 and 2018 at Seoul St. Mary's Hospital were reviewed. Total 177 patients met our eligibility criteria. The thinner group who had TMT less than the median showed shorter overall survival (OS) and progression-free survival (PFS) than the thicker group who had TMT more than median (OS; 11.0 versus 18.0months, p < 0.001, and PFS; 6.0 versus 11.0months, p < 0.001). In the multivariate analysis, the thinner group had negative associations with OS and PFS (OS; HR 2.63 (1.34-2.63), p < 0.001, and PFS; HR 2.21 (1.34-2.50), p = 0.002). We also performed propensity score matching between the thinner and thicker groups to minimize the potential bias. The thinner group showed shorter OS and PFS (OS; 13.5 versus 19.0months, p = 0.006, and PFS; 6.5 versus 9.0months, p = 0.028) and had negative associations with OS and PFS than the thicker group (OS; HR 1.90 (1.19-3.03), p = 0.008, and PFS; HR 1.70 (1.07-2.70), p = 0.026) in matched patients. Our findings suggest that TMT can be a useful prognostic biomarker for clinical outcomes in GBM patients. Further preclinical and clinical studies could help elucidate this association of sarcopenia with clinical outcomes in GBM patients.

Physical approaches to treat glioblastoma.

Glioblastoma (GBM) patients have a poor prognosis despite the use of modern synergistic multimodal treatment strategies, with a progression-free survival estimated at 7-8 months, a median survival of 14-16 months and 5-year overall survival of 9.8%. Physical methods hold the promise to act synergistically with classical treatments to improve the outcome of GBM patients. Fluorescent guided surgery with 5-aminolevulinic acid and tumor-treating fields therapy have already shown positive results in randomized phase III trials and have been incorporated in the standard management. Other techniques such as photodynamic therapy (PDT) and focused ultrasound, often combined whit microbubbles, are reaching clinical development. Several clinical trials to evaluate the feasibility and efficacy of ultrasound devices to disrupt the blood-brain barrier are ongoing. PDT enables the creation of a safety margin or treatment of non-resecable tumors. However, randomized trials are urgently required to validate the efficacy of these promising approaches. We aim to critically review physical approaches to treat GBM, focusing on available clinical trial data.

Extent of resection affects prognosis for patients with glioblastoma in non-eloquent regions

Glioblastoma (GBM) is a malignant cerebral neoplasm carrying poor prognosis. The importance of extent of resection (EoR) in GBM patient outcomes has been argued in the literature. Previous studies included tumors in eloquent regions of the brain. This confounds the role of EoR by including patients with intrinsically worse outcomes but will be over-represented in the reduced EoR category. In a homogenous group of patients in whom GTR was considered achievable, we investigated the effect of increasing EoR on survival. A retrospective review of 51 patients was undertaken. Quantitative, volumetric analysis of pre-operative and post-operative magnetic resonance image was compared with corresponding clinical details. The primary outcome measured was post-operative overall survival. Median overall survival was 18.3 months for GTR patients compared to 11.6 months for non-GTR (p = 0.025). Median pre-operative contrast-enhancing tumor volume for GTR patients was 54.7 cm3 and 24.9 cm3 for non-GTR. Post-operative median residual tumor volume was 1.1 cm3 in the non-GTR cohort. In multivariate analyses, GTR (HR [95% CI] = 0.973 [0.954–0.994], p = 0.00559) and increasing EoR (HR [95% CI] = 0.964 [0.944–0.985], p = 0.000665) remained predictors of survival. Centile dichotomization of EoR revealed 74% (HR [95% CI] = 0.351 [0.128–0.958], p = 0.0409) as the lowest threshold conferring statistically significant survival benefit. Where technically feasible, both GTR and EoR remained as independent prognostic factors for survival. GTR remains the gold standard for surgical treatment of GBM in patients, 74% being the minimum EoR required to confer survival benefit.

Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors.

This study examined the role of the ubiquitin E3-ligase RNF123 in modulating downstream NF-κB1 targets in glioblastoma (GB) tumor progression. Our findings revealed an oncogenic pathway (miR-155-5p-RNF123-NF-κB1-p50-SerpinE1) that may represent a new therapeutic target pathway for GB patients with isocitrate dehydrogenase 1 and 2 (IDH) WT (wild type). Mechanistically, we demonstrated that RNF123 is downregulated in IDH WT GB patients and leads to the reduction of p50 levels. RNA-sequencing, reverse-phase protein arrays, and in vitro functional assays on IDH WT GB cell lines with RNF123 overexpression showed that SerpinE1 was a downstream target that is negatively regulated by RNF123. SERPINE1 knockdown reduced the proliferation and invasion of IDH WT GB cell lines. Both SerpinE1 and miR-155-5p overexpression negatively modulated RNF123 expression. In clinical translational analysis, RNF123, SerpinE1, and miR-155-5p were all associated with poor outcomes in GB patients. Multivariable analysis in IDH WT GB patients showed that concurrent low RNF123 and high SerpinE1 was an independent prognostic factor in predicting poor overall survival (p < 0.001, hazard ratio (HR) = 2.93, 95% confidence interval (CI) 1.7–5.05), and an increased risk of recurrence (p < 0.001, relative risk (RR) = 3.56, 95% CI 1.61–7.83).

Activation of BDNF-AS/ADAR/p53 Positive Feedback Loop Inhibits Glioblastoma Cell Proliferation.

Despite progress in conventional treatment for glioblastoma (GBM), the prognosis remains poor due to high tumor recurrence. Therefore, identification of new molecular mechanisms is a pressing need for betterment of GBM patient outcomes. qRT-PCR was used to determine BDNF-AS expression in GBM cells. CCK-8, EdU incorporation, and caspase-3 activity assays were employed to analyze biological functions of BDNF-AS. RIP and RNA pull-down were conducted to detect the interactions among BDNF-AS, ADAR, and p53. Actinomycin D was utilized to examine the stability of p53 mRNA. ChIP and luciferase reporter assays were performed to detect transcriptional activation of BDNF-AS by p53. We found that BDNF-AS was significantly downregulated in GBM cell lines, and its overexpression inhibited GBM cell growth, and promoted apoptosis. Importantly, we illustrated that BDNF-AS coupled with ADAR protein to potentiate stability of p53 mRNA and thus upregulate p53. Interestingly, we further identified p53 as a transcription factor of BDNF-AS, activating transcription of BNDF-AS. This study firstly demonstrated that BDNF-AS acted as a tumor suppressor in GBM and the positive feedback circuit of BDNF-AS/ADAR/p53 served an important mechanism to control GBM proliferation. Targeting this auto-regulatory loop may provide a potential therapeutic strategy for GBM patients.

OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma

BackgroundPreclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents toward the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase I setting.MethodsFifteen adult patients with the first recurrence of GBM were treated with personalized SR-surgery, TTFields, and physician’s choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes.ResultsSR-surgery resulted in a mean skull defect area of 10.6 cm2 producing a median TTFields enhancement of 32% (range 25–59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%.ConclusionsTTFields therapy combined with SR-surgery and medical oncological treatment is safe and nontoxic and holds the potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

EXTH-68. INTRANASAL DELIVERY OF DRUG-LOADED LIPOSOMES SENSITIZES TUMORS TO IRRADIATION IN SYNGENEIC MODEL OF GLIOMA.

Abstract Tumor-associated myeloid cells (TAMCs) are appealing therapeutic target in glioblastoma (GBM) due to their immunosuppressive function and robust presence in the tumor tissue. We designed a lipid nanoparticle (LNP) modified with anti-PD-L1 antibody (αPD-L1) for targeted delivery to PD-L1 expressing cells within the tumor. We demonstrate that αPD-L1-LNP are effectively and specifically taken up by TAMCs. The encapsulation of dinaciclib, an inhibitor of a cyclin-dependent kinase, into αPD-L1-LNP, leads to a robust depletion of TAMCs upon local delivery. We next investigated the therapeutic relevance of non-invasive intranasal delivery of αPD-L1-LNP drug nano formulation in a GL261 syngeneic model of glioma. We show that intranasal administration of αPD-L1-LNP/dinaciclib alone did not significantly affect the survival of tumor-bearing mice, whereas a regimen combing with fractionated irradiation led to a significantly improved animal survival of mice bearing GL261 glioma over monotherapies. Histological analysis of tissue demonstrated about a four-fold increase in the uptake of nanoparticles within the tumor bed but not in the normal brain in mice treated with fractionated irradiation over the control mice. These results warrant further development and validation of intranasal delivery of therapeutic nanoformulations targeting TAMCs in preclinical animal models to improve the outcome in GBM patients.

EPID-29. THE INFLUENCE OF SOCIOECONOMIC FACTORS AND CANCER CARE RECEIVED AT DIFFERENT FACILITIES ON OUTCOME IN PATIENTS WITH GLIOBLASTOMA

Abstract BACKGROUND Younger age and higher performance status are strong positive predictors of longer survival in patients with high-grade gliomas. In many cancers, disparities in race, gender, socioeconomic background, and immigration status were shown to influence outcome. Only few studies have investigated the impact of healthcare disparities in patients with glioblastoma, with conflicting results. We hypothesized that patient-specific and healthcare system-related factors influence the utilization of healthcare and impact outcome in glioblastoma patients. METHODS This is a retrospective observational study in glioblastoma patients receiving care at a NCI-designated Comprehensive Cancer Center (CCC) or a City Hospital (CH). Patient information including demographics, insurance status, molecular characteristics, treatment details, and survival was retrieved from the medical record. RESULTS 59 patients were included (CCC n=47, PCH n=12). There were 22 females and 37 males. Median age was 63.0 years at CCC, 54.0 years at CH (p = 0.023). The two groups significantly differed by race (p=0.004), insurance status (p&lt; 0.001), median income by zip code (p=0.015), extent of resection (p=0.001), receiving radiotherapy (p=0.014), and receiving chemotherapy (p&lt; 0.001). Median overall survival (mOS) was longer at CCC (17.9 months) versus at CH (4.4 months) (p=0.021). Univariate Cox regression analyses found significantly better survival for insured vs. uninsured patients (HR 0.035, 95% CI 0.002–0.611, p=0.022) and for married/domestic partnership (M/DP) vs. non-M/DP patients (HR 0.352, 95% CI 0.141–0.879, p=0.025). Care facility, race, income, and treatment received did not emerge as significant predictors. Multivariate analysis controlling for facility and age at diagnosis showed improved survival for M/DP versus non-M/DP patients (HR 0.267, 95% CI 0.103–0.691, p=0.006). CONCLUSION(S): Insurance status and marital status emerged as significant contributors to survival. They may serve as surrogate markers for socioeconomic class and social support. Differences in Cancer Care received at different facilities may influence outcome as well.