bluuebunny/crossref_metadata_2025 huggingface dataset:
DDEL-11. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF SPATIAL HETEROGENEITY OF DRUG PENETRATION AND EXPOSURE IN THE HUMAN BRAIN AND BRAIN TUMORS
Authors: Li Jing , Wickramasinghe Charuka , Wu Andrew , Jiang Yuanyuan , Jiang Jun , Tovmasyan Artak , Kim Seongho , Sanai Nader
Published: November 2024

BACKGROUD

The difficulty in early, reliable prediction of drug penetration and exposure in the human brain and brain tumors makes development of new drugs and use of existing drugs for treating brain cancer a challenging and often unsuccessful task. We developed a physiologically based pharmacokinetic (PBPK) model platform for prediction of spatial pharmacokinetics in the central nervous system (CNS) following systemic drug administration.

METHODS

A 9-compartment CNS (9-CNS) PBPK model was developed to predict drug concentrations in brain blood, 2 brain parenchyma compartments (brain tissue adjacent to the CSF tract and deep brain parenchyma), 3 CSF compartments (ventricular CSF, cranial and spinal subarachnoid CSF), and 3 tumor compartments (tumor rim, bulk tumor, and tumor core). The pharmacokinetics in the CNS compartments were driven by plasma concentrations and governed by drug properties and CNS pathophysiology. The 9-CNS model was developed and validated with 4 drugs (abemaciclib, ribociclib, ceritinib, and temuterkib).

RESULTS

When considering tumor heterogeneity and inter-individual plasma pharmacokinetic variability following clinical standard dosing regimens, the model-predicted steady-state unbound drug tumor concentrations varied from 7.1 to 356 nM for abemaciclib, 74 to 4577 nM for ribociclib, 0.66 to 97 nM for ceritinib, and 0.8 to 288 nM for temuterkib, which were consistent with the heterogeneous drug tumor concentrations observed in glioblastoma patients. Drug penetration into the deep brain parenchyma was significantly less than that into tumors and CSF-adjacent brain tissue, particularly for strong ABCB1/ABCG2 substrate drugs. The ventricular and cranial subarachnoid CSF shared similar pharmacokinetics, while the spinal CSF pharmacokinetics was different.

CONCLUSION

A novel 9-CNS PBPK model was developed and validated for mechanistic prediction of spatial heterogeneity of drug penetration and exposure in the human brain, brain tumors, and CSF. It provides a valuable computational modeling tool to assist development and design of improved drugs or dosing regimens for brain cancer treatment.
DDEL-18. OPTIMIZED METHOD TO QUANTIFY TTFIELDS-INDUCED PERMEABILIZATION OF CELL MEMBRANES
Authors: Martinez-Paniagua Melisa , Khan Sabbir , Patel Chirag
Published: November 2024

Tumor Treating Fields (TTFields) therapy is FDA-approved for glioblastoma. Using plate-based readouts of FITC-dextran fluorescent probes in U87 human glioblastoma cells, we previously reported increased uptake of FITC-dextrans (4-20kDa) post-TTFields exposure. However, this approach is unable to distinguish FITC-dextran uptake in live-vs-dead cells post-TTFields exposure. We demonstrate flow cytometry (FC) as a more robust and economical method to quantify the amount of FITC-dextrans entering the cells. We first identified the optimal [FITC-dextran] for the FC-based approach (titration 0-6.5mg/mL). Cells were then seeded onto coverslips and exposed to 200kHz TTFields, 1-3V/cm peak-to-peak (inovitro systemTM, Novocure), or no-TTFields (control), for 24-72h. Cells were harvested and stained for 1h using 4kDa or 20kDa FITC-dextrans. Cells were washed and analyzed by FC for mean±SD fluorescence intensity, and compared by unpaired t-test. Dead cells were excluded using propidium iodide staining. In the control vs. TTFields group, 4kDa FITC-dextrans had significantly increased uptake at 24h (4.9±0.3 vs. 8.0±1.7, p=0.01), 48h (6.5±0.2 vs. 8.3±1.0, p=0.01), and 72h (5.7±0.3 vs. 8.8±1.0, p=0.001). Likewise, in the TTFields group, the 20kDa FITC-dextrans had significantly increased uptake at 24h (5.6±0.3 vs. 7.5±0.9, p=0.006), 48h (4.8±0.3 vs. 6.6±0.8, p=0.006), and 72h (5.3±0.2 vs. 11.3±2.6, p=0.004). In the TTFields group, the 20kDa FITC-dextrans had significantly increased uptake between the 24h and 72h timepoints (p=0.03). The FC-based method utilized 0.36mg of FITC-dextrans/sample, much less compared to the 1-3mg recommended for plate-based methods. Another advantage of the FC-based method was exclusion of the dead cell population after TTFields exposure. We validated a FC-based-method that is economical and can reproducibly quantify the membrane permeabilization induced by TTFields. Compared to control conditions, TTFields increase membrane permeabilization of cells that remain alive after TTFields exposure, in a time-dependent manner for the 20kDa probe.
DDDR-09. POTENTIAL OF GSPT1 AS A NOVEL TARGET FOR GLIOBLASTOMA THERAPY
Authors: Sasayama Takashi , Hamada Takeshi , Tanaka Kazuhiro , Nagashima Hiroaki , Yamanishi Shunsuke , Ueyama Takehiko
Published: November 2024

Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We have reported G1 to S phase transition 1 (GSPT1) as a novel downstream target of RAC1, which is a tumor driving and promoting molecule, and that depletions of GSPT1 as well as RAC1 induced delayed cell cycle progression in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells by genome editing and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO U87 cells). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with WT U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors due to transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those due to transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.
DDDR-26. IDENTIFICATION OF MODULATORS OF IDH INHIBITOR SENSITIVITY INIDH-MUTATED DIFFUSE GLIOMAS
Authors: Saleek Sumaiyah , Laugesen Eric , Subramani Poorani Ganesh , Tian Ruxiao , Wu Annette , Ghamrasni Samah El , Levine Adrian , Aamir Zoya , Petrecca Kevin , McBrayer Samuel , Suvà Mario , Hawkins Cynthia , Tabori Uri , Mak Tak , Fortin Jerome
Published: November 2024

Driver mutations in IDH1 and IDH2 characterize a substantial proportion of lower-grade diffuse gliomas in adults. Mutated IDH molecules cause the accumulation of D-2-hydroxyglutarate (D-2-HG), which perturbs many cellular functions, including metabolism, epigenetic regulation, and the ability to differentiate. This is notably associated with DNA and histone hyper-methylation. Recently, the newly developed IDH inhibitor, vorasidenib, was shown to delay tumor progression and the need for additional treatment in the groundbreaking INDIGO clinical trial. Nevertheless, the responses to vorasidenib were variable between patients, and so far have been established only for less aggressive disease. In addition, it is unclear to what extent vorasidenib can cause tumor regression. This highlights the need to identify molecules and pathways that control IDH inhibitor sensitivity. Towards this goal, we generated a new mouse model that combines Idh1R132H and Trp53 loss-of-function, targeted to oligodendrocyte progenitors. All the mutant mice develop diffuse gliomas that recapitulate the cardinal features of the corresponding human disease. We established multiple cell lines from these tumors, which retained expression of mutant IDH. The cells robustly produced D-2-HG, which was concentration-dependently suppressed by vorasidenib. Accordingly, vorasidenib could lower DNA methylation, and induce the expression of mature glial cell markers. To identify determinants of vorasidenib sensitivity, we performed genome-wide loss-of-function CRISPR/Cas9 functional genomics screens. In those experiments, targeting genes associated with astrocyte differentiation or Notch signaling enhanced cell fitness in the presence of vorasidenib, consistent with the anticipated effects of the drug on inducing cell differentiation. Conversely, vorasidenib-treated cells were more sensitive to the loss of regulators of cell growth and metabolism, and of some epigenetic regulators. These studies point to strategies that may enhance the efficacy of IDH inhibitors for the treatment of IDH mutated gliomas.
DDDR-28. SPHINGOSINE AND N,N-DIMETHYLSPHINGOSINE MODULATE CHOLESTEROL HOMEOSTASIS IN IDH1MUT GLIOMAS, CAUSING PRO-APOPTOTIC MEMBRANE DEGRADATION
Authors: Dowdy Tyrone , Vilamu Helena Muley , Lita Adrian , Li Aiguo , Zhang Lumin , Gilbert Mark , Larion Mioara
Published: November 2024

BACKGROUND

Previous work in our team revealed a therapeutic potential for metabolic reprogramming along the sphingolipid pathway within IDH1mut gliomas. The dosing of various IDH1mut glioma subtypes with sphingosine and sphingosine kinase inhibitor (SphKi), N,N-dimethylsphingosine (NDMS) led to the enrichment of pro-apoptotic ceramides and sphingosines while suspending the proliferation of the IDH1mut neurospheres. However, the mechanism of drug action (MOA) was not well understood. We postulated that suppressing the production of S1P production with SphKi treatment combined with the global accumulation of sphingosine and certain ceramides triggers apoptotic membrane stress in highly susceptible IDH1mut gliomas.

METHODS

We cultured and treated IDH1mut (TS603, BT142 & NCH1681) and IDH1wt (GSC923) glioma cell lines with a combination of NDMS and C17-sphingosine. We used a comprehensive multi-omics approach involving LC-MS lipidomic, RNA sequencing, immunoblotting, flow cytometry, and fluorescent microscopy.

RESULTS

Following combination treatment, a global increase in sphingosines, ceramides, and their derivatives was accompanied by a decline in cholesterol levels. The transcriptomic expression was elevated for NR1H3, MYLIP, ABCA1, and ABCG1, which regulate the trafficking and biosynthesis of membrane-associated cholesterol. In contrast, total gene expression for catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis was negatively impacted. In addition, early onset changes included an elevation in the expression of ROCK (a marker for apoptotic membrane blebbing). Moreover, fluorescent microscopy revealed that sphingosine and cholesterol tend to become associated within the cellular membranes. This interaction then saturates the plasma membrane (PM), causing apparent vesiculation, permeation, and disruption of membrane integrity.

CONCLUSION

The MOA involved concomitant attenuation of cholesterol metabolism and influx in response to membrane saturation with sphingosine-associated cholesterol. As a result, PM stress was incurred, leading to PM disintegration in a blebbing fashion. Our study revealed how reprogramming sphingolipid metabolism increases the susceptibility of IDHmut gliomas to sphingosine-associated cholesterol-induced blebbing and resulting cell death.
DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA
Authors: Shaffer Charles , Tang Nanyun , Hao Yue , Baker Angela , Berens Michael
Published: November 2024

Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.
DDDR-38. TRANSLATIONAL STEPS OF THE ANTITUMOR PEPTIDE TAT-CX43266-283 AS A TREATMENT FOR GLIOBLASTOMA: EGFR AS A TREATMENT RESPONSE BIOMARKER AND RESULTS OF COMBINATION THERAPY IN A PRECLINICAL RESECTION MODEL
Authors: Álvarez-Vázquez Andrea , Volovetz Josephine , San-Segundo Laura , Cerveró-García Pilar , Flores-Hernández Raquel , Ollauri-Ibáñez Claudia , Segura-Collar Berta , Hubert Christopher G , Sánchez-Gómez Pilar , Pollard Steven M , Lathia Justin D , Tabernero Arantxa
Published: November 2024

Glioblastomas (GBM) are the most malignant primary brain tumors, and they remain incurable. Despite the current standard of care (surgical resection of the tumor and administration of chemotherapy and radiotherapy) some GBM stem cells (GSCs) remain in the brain parenchyma causing tumor recurrence. The Src-inhibitory peptide TAT-Cx43266-283 has shown promising antitumor results in GBM preclinical models, reducing GSC viability and increasing survival in GBM-bearing mice. Here we have investigated some of the main gaps to overcome when translating preclinical results to the clinic, to promote the progress of TAT-Cx43266-283 as a clinical therapy to fight GBM. First, we investigated biomarkers of treatment response to design a more targeted therapy. We assessed cell viability after treatment with TAT-Cx43266-283 in 13 patient-derived GSC lines and we found a stronger treatment response in those GSCs that had alterations in the Epidermal Growth Factor Receptor (EGFR). This was further confirmed in several murine GBM lines. Importantly, we found that treatment with TAT-Cx43266-283 was more effective in vitro than temozolomide or the classical EGFR inhibitor, erlotinib. Moreover, we showed that EGFR participates in TAT-Cx43266-283 response together with Src, by decreasing EGFR and EGFRvIII activity in some GSCs and increasing survival in mice bearing tumors with EGFR alterations. Next, we studied the effect of TAT-Cx43266-283 in a clinical context by administering it in a murine model of tumor resection. We analyzed the histopathology of this GBM model, uncovering histological features typical of human GBM. We found that resection alone improved, although not significantly, GBM-bearing mice survival. However, tumors that regrew after resection exhibited more aggressive features. Importantly, the combination of tumor resection and TAT-Cx43266-283 achieved better survival outcomes and showed reduced invasive features. Altogether, these results serve as a base for future clinical investigations and support the therapeutic potential of TAT-Cx43266-283 as a treatment for GBM.
DDDR-42. LEVERAGING GENOME-WIDE CRISPR/CAS9 KNOCKOUT DRUG SCREENS TO IDENTIFY SENSITIZERS FOR PROTEOSOME INHIBITORS IN GLIOBLASTOMA
Authors: Anand Alisha , Shaikh Muhammad Vaseem , Chokshi Chirayu , Brakel Benjamin , Maich Will , Grewal Shan , Venugopal Chitra , Singh Sheila
Published: November 2024

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis despite aggressive treatment. Patient outcomes remain abysmal with 95% of patients relapsing and a median overall survival of 15 months. This necessitates the rapid search for personalized therapeutics and agents to enhance current treatments. One pathway that demonstrates dysregulated functioning is the ubiquitin-proteasome pathway (UPP). Literature has shown that UPP dependent proteolysis remains constitutively upregulated in cancer cells leading to the rapid degradation of proteins that regulate oncogenic pathways. Despite robust preclinical evaluations for the usage of proteasome inhibitors against GBM, most proteasome inhibitors failed in clinical trials, indicating resistance. We conducted an unbiased genome wide CRISPR-Cas9 screen in HAP1 cells treated with the proteasome inhibitor, Bortezomib (BTZ), to identify genes leading to a BTZ-resistant phenotype. We identified several genes that when perturbed, sensitized cells to BTZ including N-glycanase-1 (NGLY-1), Nuclear factor Erythroid 2-Like-1 (NFE2L1), and DNA damage inducible 1 homolog 2 (DDI2). Herein, we sought to evaluate the effects of perturbing these identified genes in our patient derived GBM cell lines by utilizing CRISPR/Cas9 knockout technology in vitro and in vivo. The generation of NGLY-1, DDI2, and NFE2L1 KO cell lines demonstrated functional sensitivity to the proteasome inhibitor Marizomib (MZB) as observed through a significant reduction of the IC50 in the KO cell lines compared to an adeno-associated virus integration site 1 (AAVS1) control. Functional evaluation also demonstrated reduced proliferation capacity and sphere formation in our KO GBM lines. Ongoing in vivo work will aim to evaluate the mitigation of this resistant pathway in our NSG mouse models orthotopically transplanted with our patient derived KO cell lines. In an ongoing collaborative effort, we aim to functionally assess a novel small molecule NGLY-1 inhibitor for preclinical sensitivity to MZB in our in vitro and in vivo models.
EPID-15. INPATIENT CARE COSTS AND ASSOCIATED REIMBURSEMENTS FOR PATIENTS WITH LEPTOMENINGEAL DISEASE: A REAL-WORLD ANALYSIS
Authors: Ozair Ahmad , Mansouri Alireza , Grossman Stuart
Published: November 2024

INTRODUCTION

Leptomeningeal disease (LMD) is an increasingly significant cause of cancer-related morbidity, mortality, and economic burden. While healthcare costs associated with brain metastases (BMs) have been well-described, minimal economic literature exists for LMD. This study sought to evaluate inpatient care costs (IPCCs) and reimbursements for LMD patients using a contemporary US claims database.

METHODS

This retrospective study, reported following STROBE guidelines, included adult LMD patients (aged 18-65 years) receiving inpatient care during January 2016 to December 2021 in TruvenHealth MarketScan Commercial Claims and Encounters Database, currently the largest US commercial insurance database. Patient selection using ICD-10 codes, data management, and statistical analyses were performed in Stata/SE18.0. Demographic, clinical, and financial attributes were summarized through descriptive statistics. IPCC measures were adjusted using 2023 Consumer Price Index Medical Care component. Primary study outcome was adjusted gross total payments (total IPCC). Given skewness in IPCC, log-transformation was carried out, followed by multivariable linear regression using socio-demographic, clinical and insurance-related characteristics to identify significant covariates.

RESULTS

A total of 1047 inpatient admissions across 1010 LMD patients were included. 43.8% (N=442) had brain metastases (BM) concomitantly present while 56.2% (N=568) did not. Primary tumor associated with LMD comprised of: lung and/or lower respiratory tract cancer (18%), breast cancer (6.6%), and melanoma (6.1%). 54.8% (N=554) did not have any bone metastases and 78.6% (N=794) did not have any liver metastases. Per inpatient admission, median adjusted values of gross total payments were $32603.6 (IQR $19967-64960) and gross payments to principal physician $1119.26 (IQR $532.41-2919.78), being 3.4% of total payments. Covariates associated with significantly higher total IPCC included age, male sex, length -of-stay, whole brain radiotherapy, and admission year, while cancer from lung and melanoma, medical and psychiatric admission (versus surgical), and drug claims capture were associated with significantly lower IPCC.

CONCLUSIONS

Contemporary IPCCs for LMD patients in US are substantial but driven minimally by payments to principal physician for services rendered.
EPID-27. THE INCIDENCE OF BRAIN METASTASIS IN GASTROINTESTINAL CANCER ACCORDING TO PRIMARY SITE AND STAGE: A 15-YEAR SINGLE INSTITUTIONAL ANALYSIS
Authors: Barcelona Marc Vincent , Kataki Kaushik Jagannath , Rahman Fadwa Abdel , Schultz David , Millar Barbara-Ann , Conrad Tatiana , Taremi Mojgan , Kongkham Paul , Elimova Elena , Deng Yangqing , Yan Michael Ming
Published: November 2024

Gastrointestinal (GI) cancers are a diverse group of cancers including pancreatic, gastric/gastroesophageal junction/esophageal (G/GEJ/E), colorectal (CRC), hepatocellular (HCC), biliary tract (BT), and anal origin cancers. The risk of developing brain metastasis (BrM) is not well characterized. The aim was to determine the incidence of BrM among all GI cancer patients at Princess Margaret Hospital (PM). We included patients diagnosed with GI cancer presenting from 2005-2020, captured prospectively in our institutional registry. These patients were cross-referenced with our radiotherapy database, where radiotherapy for brain metastases (BrM) was used as a proxy for the brain metastases development. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk. Overall survival (OS) was estimated using the Kaplan Meier method. The registry accounted for 22,188 patients. The median age of the cohort was 64. Most common primary sites are CRC adenocarcinoma, pancreatic adenocarcinoma, G/GEJ/E adenocarcinoma were 31.52%/11.71%/10.25%. The 15-year CI for BrM for the entire cohort was 1.65%, and for CRC, small bowel, anal, pancreatic, G/GEJ/E, HCC, and BT cancers were 2.69%/2.49%/1.30%/0.5%/3.52%/ 0.05% /0.4% (p < 0.001) and Stage I-IV disease were 0.39%/0.81%/1.2%/3.1%, respectively (p < 0.001). 5 year CI for HER2 positive G/GEJ/E patients was 19.5%. Median OS from initial presentation for those with BrM was 25.13 months. On univariable analysis, chemotherapy receipt [HR 1.916, p < 0.001], Stage IV at presentation [HR 3.991, p < 0.001], and G/GEJ/E primary [HR 1.357, p < 0.001] predicted for higher risk of BrM. Multivariable analysis confirmed that receipt of chemotherapy and Stage IV disease predicted a higher risk for BrM and pancreatic, HCC, and BT cancers predicted for lower BrM. We observed that among patients diagnosed with GI cancers, Stage IV disease predicted higher risk for developing BrM and were more likely to receive chemotherapy.
EPID-29. EPIDEMIOLOGICAL CHARACTERIZATION OF BRAIN METASTASES IN MELANOMA: A LARGE POPULATION BASED-STUDY FROM 2014-2024
Authors: Kalluri Anita , Kramer Patrick , Parker Megan , Jiang Kelly , Materi Joshua , Azad Tej , Kamson David , Redmond Kristin , Warrier Govind , Lipson Evan , Ye Xiaobu , Bettegowda Chetan , Rincon-Torroella Jordina
Published: November 2024

Brain metastases (BM) are the second most common cause of mortality in metastatic melanoma. Despite increased screening, mortality remains substantial. Additionally, population-based studies of melanoma BM capture only synchronous metastases, therefore up-to-date epidemiological and survival studies may better inform screening and management strategies. Thus, we retrospectively analyzed the TrinetX Oncology dataset to study the prevalence and survival patterns of patients with melanoma BM. Data from 13,505 patients with histologically-confirmed melanoma was extracted. Demographic and clinical parameters were compared between patients with and without BM via t-test and chi-squared analysis. Overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses after cohorts were propensity-matched for age, sex, race, ethnicity, stage, extracranial metastases, excision of skin lesions, radiation, and antineoplastic utilization. In our study, the prevalence of BM was 7.3% (9.2% precocious, 22.5% synchronous, 68.3% metachronous). Compared to patients without BM, patients who developed BM were more often male (p<0.0001), non-Hispanic (p<0.0001), White (p<0.02), and presented with advanced-stage disease (p<0.0001). Patients with unspecified malignant melanoma (p<0.0001) and nodular melanoma (p<0.0001) were more likely to develop BM compared to those with other histological subtypes. Additionally, patients with BM were more likely to have ulceration (p<0.0001) and extracranial metastases (p<0.0001). Skin excision procedures were less common in patients with BM (p<0.0001), whereas radiotherapy and antineoplastics were more common. When assessed from melanoma diagnosis, patients who developed BM any time along their disease course had reduced OS (HR(95% CI): 2.265(1.934-2.653)). When assessed from metastatic onset, patients with BM had reduced OS compared to those with only extracranial metastases (HR (95% CI): 2.197(1.883-2.563)). Synchronous BM were associated with decreased OS compared to metachronous BM when assessed from melanoma onset (HR(95% CI): 0.6(0.442-0.815)), but there was no survival difference after BM development. In conclusion, BMs decrease OS in melanoma. Our findings may inform screening and management of patients at risk for melanoma BM.
EPID-34. THE EFFECT OF ANTIDEPRESSANT THERAPY ON GLIOBLASTOMA SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sun Yifei , Hamo Mohammad , Hagan Emma O’ , Atchley Travis , Estevez-Ordonez Dagoberto
Published: November 2024

BACKGROUND

Symptoms of depression are highly prevalent among patients with glioblastoma (GBM) and have been associated with poor outcomes. In addition to managing depression symptoms, preclinical and clinical studies suggest that antidepressants may inhibit GBM progression and may be associated with improved outcomes. However, the effect of antidepressants on survival is unknown and results from existing studies are conflicting.

OBJECTIVE

We conducted a systematic review and meta-analysis to investigate the effect of antidepressant therapy on GBM survival.

METHODS

We searched PubMed, Embase, Scopus, PsycINFO, and Web of Science from inception to March 2024 for studies assessing the overall survival of patients with GBM treated with antidepressants. Prespecified Hazard ratios (HR), 95% confidence interval (CIs), median overall survival, and patient characteristics were extracted. Results were combined using a restricted maximum-likelihood estimation random-effects model.

RESULTS

We identified 6 observational studies meeting inclusion criteria with 8269 patients. Of these, 1093 (13%) were treated with antidepressant therapy at some point after their GBM diagnosis. Antidepressant therapy was not significantly associated with overall survival (HR 1.27, 95% CI 0.90-1.79, p=0.17). In a sub-analysis of studies that specified whether SSRIs were utilized, SSRI usage specifically was also not associated with overall survival (HR 1.08, 95% CI 0.58-2.03, p=0.81) We observed considerable heterogeneity (I2 = 92.7%, p<.001).

CONCLUSIONS

Antidepressants were not significantly associated with overall survival in patients with GBM. However, our meta-analysis was limited by significant heterogeneity observed across studies. The effect of antidepressants on outcomes in patients with GBM remains uncertain. We observed conflicting results in the literature, with some studies suggesting decreased survival. Therefore, the role of antidepressants in patients with GBM warrants further investigation.
DISP-06. THE IMPACT OF SOCIAL DETERMINANTS OF HEALTH ON TREATMENT DELAYS FOR GLIOBLASTOMA
Authors: Cioffi Gino , Gratzl Samuel , Dmukauskas Mantas , Waite Kristin , Sloan Andrew , Mammoser Aaron , Stucky Nicholas , Barnholtz-Sloan Jill
Published: November 2024

Social determinants of health (SDOH) contribute to treatment delays for a variety of diseases. However, the impact of SDOH on delays in treatment for glioblastoma (GBM) is not well established. Utilizing the Truveta database, which includes electronic health records, claims, linked SDOH data, and medication dispense data for a collective of US health systems, we evaluated individuals diagnosed with GBM from 1/1/2018-5/16/2024 who received either surgery, radiation, or temozolomide. Univariable and multivariable logistic regression modeling was performed to assess the odds of experiencing a delay in surgery (>7 days after diagnosis), radiation (>30 days after diagnosis), or temozolomide (>30 days after diagnosis). Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) are reported. Models were assessed for demographic (sex, age, race) and SDOH factors (education, income, social support, transportation, housing stability). At the univariable level, college attendance and single-member household were associated with delays in surgery but were not significant in the multivariable model. Individuals diagnosed with GBM at ages of 45-64 and 65+ were less likely to experience delays in surgery than individuals ages 18-44 (45-64 aOR (95%CI): 0.58(0.38-0.89), 65+ aOR (95%CI): 0.42(0.25-0.71)). Additionally, individuals with an estimated yearly income of $60,001-$120,000 were 61% more likely to experience delays in surgery compared to individuals with an estimated income of <$40,000 (aOR (95%CI): 1.61(1.16-2.24)). In univariable analyses, male sex, age at diagnosis of 18-44, college attendance, and an estimated income >$120,000 were associated with delays in radiation. However, no significant factors were associated with delays in radiation after adjustment. Individuals ages 45-64 and 65+ were less likely to encounter delays in temozolomide than individuals ages 18-44 (45-64 aOR (95%CI): 0.64(0.46-0.88), 65+ aOR (95%CI): 0.62(0.43-0.91)). Understanding how SDOH impact treatment patterns provides vital insight on diverse factors that impact patient care.
DISP-10. RACIAL AND SOCIOECONOMIC DIFFERENCES IN CLINICAL AND ACCESS TO CARE OUTCOMES IN NEUROSURGICAL-ONCOLOGY PATIENTS
Authors: Prabhu Ashna , Perryman Travis , Harper Stuart , Carson Amani , Dudley Lindsey , Delgadillo Alondra , Gor Aidan , Patel Kunal
Published: November 2024

BACKGROUND

Large database studies have identified racial and socioeconomic differences in neurosurgical-oncologic outcomes. For clearer insights and understanding, more detailed and prospective evaluation is needed.

METHODS

We retrospectively analyzed a database of 1475 patients undergoing surgery for CNS tumors over 5 years. Multivariate analysis, specific to various pathologies, was conducted to identify demographic and socioeconomic factors (including age, sex, racial identity, primary language, insurance status, and income estimate) associated with access to care and clinical outcomes. Additionally, prospective patient-centered interviews were conducted on neuro- oncology patients to qualitatively explore reasons for disparities in healthcare.

RESULTS

Significant associations were found between racial identities (White n=911; Hispanic n=285; Asian n=206; Black n=74) and sex (ANOVA p 0.0043), age (p<0.0001), income estimate (p<0.0001), primary language (p<0.0001), and insurance status (p<0.0001). Among different pathologies, presentation to the ED, rather than outpatient setting, was consistently associated with a non- English primary language (p=0.0312) and Medi-Cal insurance (p=0.0029). Time from imaging diagnosis to neurosurgical consultation was associated with non- English primary language (p=0.0262) and Medi-Cal (p=0.0030). Delay between recommendation for surgery and date of surgery was significant in Black patients (p=0.0112). A non- English primary language was negatively associated with having a gross total resection (p=0.0087). Notably, adjuvant treatments were less likely for those with non-English primary language (p=0.0203), Black race (p=0.0049), and Medi-Cal coverage (p=0.0014). Cox regression analysis identified only age (p<0.0001) as a predictor of poorer overall survival in oncologic cases. Prospective interviews identified cultural, economic (work- related), and healthcare navigation issues as reasons for differences in access to care.

CONCLUSIONS

Across the spectrum of neurosurgical oncology diagnoses, racial and socioeconomic factors independently associate with access to care but not clinical outcome variables. Further investigation is needed, particularly in patients with non- English primary languages and cultural attitudes towards chemotherapy and radiation therapy.
DISP-17. OUTCOMES, CLINICAL AND MOLECULAR CHARACTERISTICS OF HISPANIC PATIENTS WITH IDH WILDTYPE GLIOBLASTOMA
Authors: Blaquier Juan , D’Angelo Fulvio , Tejera Dalissa , Nasany Ruham , Kushnirsky Marina , Hill Colin , Iavarone Antonio , de la Fuente Macarena
Published: November 2024

BACKGROUND

Knowledge about outcomes in Hispanic patients with gliomas is scant and mainly derived from tumor registries. IDH wild-type glioblastomas (GBM) are the most common and aggressive malignant primary brain tumor. Hispanics account for 19% of US population, reaching 29% in Florida and 65% in Miami-Dade County. As a reference center for GBM serving the community of South Florida we provide care for many Hispanic patients. Herein, we aim to describe the clinical and molecular features, including RNA seq analysis of Hispanic vs non-Hispanic patients with IDH wild-type GBM.

METHODS

Retrospective study of adult patients with diagnosis of IDH Wild-type Glioblastoma, who had NGS testing, treated at University of Miami.

RESULTS

179 patients were included, 63 (35%) were Hispanic. 41 (65%) of Hispanic patients were males as compared to 65 (56%) of the non-Hispanics. Median age at diagnosis was 54 years (45-67) for the Hispanic vs 62 (54-72) years for non-Hispanic, p=.002. With a median follow up of 17 months (CI 95% 14-19), median overall survival for Hispanic patients was 22 months (18-25) and 23 months (18-28) for non-Hispanics, p=.99. 42 (23%) patients were enrolled in clinical trials, of whom 21 (50%) were Hispanic, meaning 33% of Hispanic patients enrolled. The molecular characteristics from these patients by next-generation sequencing, including RNA seq, are being analyzed.

CONCLUSIONS

In our series of IDH wild-type Glioblastomas, Hispanic patients were significantly younger at diagnosis compared to non-Hispanic patients, but there were no differences in overall survival. 33% of Hispanic patients were enrolled in clinical trials. As the latest growing ethnic group in the USA, major efforts have to be made to better understand the disease characteristics and outcomes of this particular population. To our knowledge this will be the first report of the molecular characteristics by NGS from Hispanic patients with GBM.
IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER
Authors: Pathak Asmita , Palavalasa Sravya , Ciervo Erika , Van Den Knott Maxon Berg , Susic Nikola , Shah Khushi Hemendra , Colon Bruno , Chin Diana , Zhou Yadi , Cheng Feixiong , Lyssiotis Costas , Watson Dionysios C , Wahl Daniel , Ceccarelli Michele , Shah Ashish , Lathia Justin D , Bayik Defne
Published: November 2024

Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.
IMMU-05. TNFR2 IS A NOVEL MARKER OF EXHAUSTION AND TNFR2 BLOCKADE IMPROVES SUBCUTANEOUS TUMOR CONTROL
Authors: Hoyt-Miggelbrink Alexandra , Polania Jessica Waibl , Mohan Aditya , Wachsmuth Lucas , Lorrey Selena , Lerner Emily , Wilkinson Daniel , Hardigan Andrew , Blandford Emily , Hotchkiss Kelly , Hemmers Saskia , Quackenbush Sarah Cook , Ayasoufi Katayoun , Fecci Peter
Published: November 2024

Checkpoint inhibitors have been successful in various tumors. However, these treatments have failed in glioblastoma. Approaches harnessing the immune response are hindered by multiple factors, including T cell exhaustion. TOX is particularly important for the transcriptional and epigenetic reprogramming of exhausted T cells. While it is known that NFAT is upstream of TOX, our understanding of the upregulation of TOX remains incomplete. We hypothesized that tumor necrosis factor (TNF) could be involved in the upregulation of TOX as TNF can lead to the translocation of NFAT into the nucleus. We observed significant upregulation of the anti-inflammatory TNF receptor type II (TNFR2) in tumor-infiltrating T cells. This local upregulation mimics expression patterns of canonical exhaustion markers. TNFR2 expression is correlated with markers of exhaustion, including PD1, TIM3, and TOX. Furthermore, TNFR2 knock out (KO) CD8 T cells have significantly lower TOX expression, without the concomitant decrease of TIM3. Whereas previous studies have linked TIM3 and TOX expression, these data suggest that TIM3 and TOX are regulated independently. We utilized bulk RNA-sequencing to assess transcriptional regulation of WT and KO T cells and detected a significant reduction of T cell exhaustion and immune checkpoint pathways in TNFR2 KO T cells. Various exhaustion-related transcription factors and coinhibitory markers were significantly reduced. In contrast, a significant increase in AP1 transcription factors, commonly associated with T cell effector functions, was detected. Given this reduced exhaustion profile, we subsequently investigated the influence of TNFR2 on tumor burden. TNFR2 KO mice had significantly lower tumor burdens following subcutaneous tumor challenges. We subsequently treated mice with a TNFR2 antagonist. While the antagonist alone was not sufficient to improve tumor control, combination with anti-PD1 significantly reduced tumor volumes. These data provide evidence for a novel marker of exhaustion that could result in a unique therapeutic strategy.
IMMU-07. THE IMMUNE LANDSCAPE OF PEDIATRIC BRAIN TUMORS: A TRANSCRIPTOMIC ANALYSIS
Authors: Frederico Stephen , Raphael Itay , Nisnboym Michal , Huq Sakibul , Shlegel Brent , Sneiderman Chaim , Jackson Sydney , Jain Anya , Rood Brian , Pollack Ian , Hwang Eugene , Rajasundaram Dhivyaa , Kohanbash Gary
Published: November 2024

Despite standard-of-care therapy, pediatric brain tumors are now the leading cause of cancer-related death in children, highlighting an urgent need for the development of new treatments. Immunotherapy is actively being evaluated as a therapeutic approach to pediatric brain tumors, however, more research is needed to reveal additional antigenic targets that exist in these malignancies. In this study, our team performed a transcriptomic analysis of pediatric brain tumor RNA sequencing data within the Children’s Brain Tumor Network (CBTN) to identify intra and extracellular antigens that are highly expressed across major tumor types. Interestingly, our team observed that most tumors had high gene expression of a group of antigens that were unique to that specific tumor type. Specifically, our analysis revealed that diffuse midline gliomas (DMGs) highly expressed the extracellular antigens CA9, CTCFL, and ST8SIA1, whereas atypical rhabdoid tumors (ATRTs) highly expressed MUC1 and TEK. Other tumors that displayed high gene expression for a variety of antigenic targets included H3-wildtype high-grade gliomas (HGGs), and ependymomas (EPNs). Strikingly, we observed minimal difference in antigen expression in primary tumors when compared to patient-matched recurrences. Beyond antigen expression, we evaluated the expression of antigen processing machinery (APM) which includes major histocompatibility complexes (MHCs). Our findings revealed that DMGs had the lowest level of APM expression, however, these tumors uniquely expressed high levels of the immune checkpoints ADORA2A, CD276, and KLRC1. Contrarily, ATRTs showed a high expression of immune checkpoints CD274 (PD-L1), PVR, and CD80. Other tumors included in our analysis had unique expression patterns of antigen, as well as APM and immune checkpoints. Our findings illustrate that pediatric brain tumors have distinct expression patterns of antigens, APM, and immune checkpoints that are specific to tumor type, emphasizing diverse, rather than general, immunotherapeutic approaches must be considered for childhood brain tumors.
IMMU-36. MULTI-OMIC CHARACTERIZATION OF A SYNGENEIC MOUSE CANCER STEM CELL MODEL OF GBM FOR PRECLINICAL APPLICATIONS
Authors: Heemskerk Kyle , Assaf Samir , Hao Xiaguang , Meode Mathieu , Kala Smriti , Pemberton James , Mirzaei Reza , Cairncross J Gregory , Forsyth Peter , Yong V Wee , Weiss Samuel , Zemp Franz , Artee Luchman H
Published: November 2024

Glioblastoma (GBM) is resistant to many therapies including immunotherapies. There is an urgent need to explore the role of the microenvironment in resistance to therapy with tailored pre-clinical models. Using multi-omic approaches we describe a syngeneic cancer stem cell mouse model of GBM, with a spontaneous amplification of Igf2. We investigate whether Igf2 influences tumour and microenvironment cells to promote immunosuppression in GBM. Three cell lines were previously established from spontaneous brain tumours in C57Bl/6 Trp53+/-/Nf1+/- mice and maintained under neural stem cell culture conditions. Whole genome sequencing (WGS) was used to determine single nucleotide, copy number, and structural variation, revealing loss of both copies of Trp53 and Nf1 in all three cell lines. However only one cell line, mBT0309, developed tumors when orthotopically allografted. Analysis of genomic alterations and transcriptomics revealed that mBT309 exhibits amplification of the Igf2 loci and overexpression was confirmed at the RNA and protein level. Spatial and single cell transcriptomics showed that Igf2 is overexpressed in mBT0309 allografted tumours and correlated with specific transcriptomic programs. A high-parameter Imaging Mass Cytometry (IMCTM) panel was used for spatial proteomic analysis, to monitor the development of tumours in a time-course experiment. In vitro growth characteristics and stem marker expression in both transcriptomic and spatial IMC data suggest that high levels of Igf2 may regulate GBM stemness features. Analysis of human GBM datasets revealed that Igf2 amplified tumours have reduced CXCL11 expression. These findings suggest that high levels of Igf2 may influence immunosuppression by reducing T-cell recruitment. This syngeneic immunocompetent GBM stem cell model harbouring Igf2 amplification adds to the suite of models to study the GBM microenvironment and its role in immunosuppression and resistance to therapy.
IMMU-40. INVESTIGATING THE ROLE OF MUTATIONAL BURDEN IN TUMOR IMMUNOGENICITY USING A PRE-CLINICALMLH1-DEFICIENT GLIOBLASTOMA MODEL
Authors: Haynes Tuesday , Breen Kevin , Zhang Meili , Song Hua , Davis Dionne , Briceno Nicole , Wong Zalman , Li Aiguo , Watanabe Masashi , Gilbert Mark
Published: November 2024

BACKGROUND

Although there is an established correlation between tumor mutational burden (TMB) and response to immune checkpoint inhibition (ICI) in many cancers, such an association has not been definitively shown in high-grade gliomas. Most studies of ICI therapy in gliomas, including glioblastoma (GBM), have failed to demonstrate efficacy, with the exception of hypermutated cases resulting from rare inherited defects in mismatch repair (MMR) genes. We sought to investigate the association of TMB to immune response using a syngeneic murine model with a spectrum of mutational burdens.

METHODS

We used CRISPR-Cas9 to knockout the MMR gene Mlh1 in the murine glioma model SB28, an ICI-resistant cell line with a very low mutational burden (108 non-synonymous mutations).

RESULTS

Single-cell sorted Mlh1 knockout SB28 clones revealed a two- to six-fold increase in TMB. Importantly, loss of Mlh1 also brought about global changes in immune- and inflammatory-related gene expression in vitro, without correlation to increasing TMB. While all clones had the same rate of in vitro proliferation, flank injection of a high TMB vs a low TMB SB28 Mlh1 knockout clone resulted in similar survival benefits compared to Mlh1 wildtype SB28.

CONCLUSIONS

These preliminary results suggest that, although disruption of the MMR system may result in heightened tumor immunogenicity, elevated TMB may not be the sole significant determinant. We are currently investigating tumor proliferation after flank injection in immunocompromised mice to confirm that slowed growth is immune-related, as well as clone-specific response to ICI treatment. We are also exploring the role of specific cytokines/chemokines in conferring this survival advantage and potential immune response. By generating a GBM model of varied mutational burdens and immune profiles and comparing to the baseline SB28 cell line, we can interrogate the relative significance of TMB in tumor immunogenicity and ICI response.