bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-82. TUMOR ORGANOID PREDICTED THERAPEUTIC RESPONSES TO NOVEL EPIGENETIC DRUGS VIA HIGH-THROUGHPUT SCREENING
Authors: Bae Goeun , Palacios Milagros Suarez , Powell Reid T , Stephan Clifford C , Li Xiaonan , Du Yuchen 
Published: November 2024

Abstract

INTRODUCTION
The treatment choices for pediatric brain tumors are still very limited. Epigenetic therapy emerges as a promising option recently. The lack of in vitro models that represent tumors in vivo and can be scalable for large scale drug screening is major barrier. We have developed tumor organoids from patient-derived orthotopic xenograft and performed a multi-stage high throughput screening for single or combined epigenetic agents and radiation therapy in tumor organoids.

METHOD
Primary xenograft tumor cells were cultured in matrix and cancer stem cell culture medium in 384-well plates. Radiation sensitivity was examined at 5 different doses. Epigen40 (40 drugs/compounds) targeting various epigenetic modifications was used alone to identify agents with the most cell killing (4 doses for up to 19 days). The drugs that showed partial activity were combined with radiation (at 5 doses) to evaluate additive or synergistic effects. The anti-tumor efficacy of selected drug was then evaluated in vivo.

RESULTS
The conditions of organoid growth and screen variability were optimized. 7 tumor organoids including 4 glioblastomas and 3 medulloblastomas were successfully established and characterized. The different radio-sensitivities were observed among these models. 7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Chaetocin, methyltransferase SUV39H inhibitor, demonstrated broadly active and highly potent inhibition across all 7 tested organoids. In addition, bioinformatic analysis identified a subset of epigenetic inhibitors combined with radiation that produced additive anti-tumor activities in vitro. Unfortunately, in vivo treatment of Chaetocin (0.25mg/kg) didn’t convey consistent anti-tumor effects as shown in vitro whereas a high risk of drug toxicity to the mice.

CONCLUSION
Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified.
QOL-16. POSTOPERATIVE MOTOR FUNCTION AND PROCESSING SPEED PREDICT QUALITY OF LIFE IN PATIENTS WITH GLIOBLASTOMA AT CHRONIC-PHASE
Authors: Nakada Mitsutoshi , Nakajima Riho , Kinoshita Masashi 
Published: November 2024

Abstract
The quality of life (QOL) in patients with glioblastoma (GBM) should be paid attention. The aim of this study is to identify brain functions that influence the QOL of patients with GBM by objectively assessing neurocognitive functions. Data from 40 patients with newly diagnosed GBMs were analyzed. All patients completed the assessment of various neurological and neurocognitive functions and QOL at 6 months postoperatively. QOL was assessed using the 36-Item Short Form Survey (SF-36). In the SF-36, the physical, mental, and role and social component summary (PCS, MCS, and RCS, respectively) scores were calculated. Multiple logistic regression analyses and chi-square tests were used to evaluate the association between SF-36 scores and brain functions. The MCS was maintained, whereas the PCS and RCS scores were significantly lower in patients with GBMs than in healthy controls (p=0.0081 and p&lt;0.0001, respectively). Among a variety of brain functions, motor function and processing speed were significantly correlated with PCS and RCS scores, respectively (p=0.0048 and p=0.030, respectively). Patients whose PCS or RCS remained stable had a higher probability of motor function or processing speed preservation than those whose RCS or PCS decreased (p=0.0026). Taken together, motor function and processing speed may be predictors of QOL in patients with GBMs.
SURG-14. PATTERNS OF PROGRESSION OF TEMPORAL LOBE GLIOBLASTOMAS: EVIDENCE FOR THE ROLE OF TEMPORAL LOBECTOMY
Authors: Price Stephen , Gurung Binay , Nazar Thaaqib , Mair Richard , Joannides Alexis , Santarius Thomas , Matys Tomasz 
Published: November 2024

Abstract
Glioblastomas extend beyond the contrast-enhancing tumor, and supramaximal resections into non-enhancing (NE) tumor improves survival. Yet, supramaximal resection is difficult to achieve in most cases. For temporal lobe tumors, supramaximal anterior temporal lobe resection is feasible and safe. Case series have shown a survival advantage by resecting the anterior temporal lobe. This study aims to explore patterns of tumor progression in temporal lobe glioblastomas and whether the presence of NE tumor in the temporal tip could be used as a biomarker to predict the site of progression. We searched a single institution tumor database looking for patients who had glioblastomas in the temporal lobe, who underwent complete resection of enhancing tumor, and went on to have chemoradiotherapy. Patients needed to have imaging demonstrating first progression. We determined pre-operatively if NE tumor had extended into the temporal tip. At progression, the direction of tumor progression was recorded and assessed if it would have been resected should a lobectomy have been performed. We identified 55 patients that fulfilled our entry criteria (mean age 57.7 years, range 19.6-72.9; 37 male). In 16 cases, the anterior temporal lobe was resected; these patients were not used in further assessments. In 25 cases (64.1%), the tumor progressed into the residual anterior temporal lobe. In 16 cases (41.0%), a lobectomy would have encompassed the area of progression. NE tumor was seen in the tip in 28 cases (71.8%). This could predict progression into the anterior temporal lobe with a sensitivity of 76.2% (95%CI: 54.9-90.6%) and specificity of 33.1% (95%CI: 11.8-61.6%). The likelihood ratio of tumor progression was 1.14 (95%CI: 0.75-1.74). We conclude that temporal lobe glioblastomas most commonly progress into the anterior temporal lobe, but NE tumor is not a suitable predictive biomarker. Developing suitable biomarkers and biomarker-driven trials of temporal lobectomy for glioblastomas are needed.
SURG-50. CLINICAL EXPERIENCE AND PATHOLOGICAL FEATURES IN AUTOPSY CASES TREATED WITH TUMOR TREATING FIELDS
Authors: Tamai Sho , Kinoshita Masashi , Nambu Kosuke , Tanaka Shingo , Nakada Mitsutoshi 
Published: November 2024

Abstract

BACKGROUND
Since 2017 Tumor Treating Fields (TTF) was approved for primary glioblastoma in Japan. In this study, we reviewed clinical experience and the pathological characteristics of autopsy cases treated with TTF.

METHODS
From March 2018 to April 2022, 67 patients (36 males and 31 females, median age 68 years) with primary glioblastoma, IDH-wild type treated at our institution were included in the analysis.

RESULTS
Twenty-eight patients (19 males and 9 females, median age 66 years) met the TTF indication criteria for induction, 19 cases (67.9%) were 65 years or older, and 14 cases (50.0%) indicated MGMT promoter methylation. The mean duration of TTF treatment was 7.2 months. The main reasons for discontinuation were tumor recurrence in 11 patients (40.7%), skin symptoms in 8 patients (29.6%), and psychological distress in 6 patients (22.2%). Only 12 patients (42.9%) underwent TTF treatment over 18 hours per day, because of discomfort of wearing pad and concern about srrounding. Median PFS and OS in the used patients were 9.9 and 17.7 months, respectively. Autopsies were performed in 3 of the 16 deaths. Histopathological examination of tumor specimen indicate that the Ki-67 labeling index was higher in brainstem (33.6%) than in the supratentorial primary lesion (23.6%).

DISCUSSION
Comparing to the previous report (Stupp R et al., JAMA. 2017), our cases contained a large number of patients over 65 years old with shorter mean duration of TTF treatment, and shorter OS. After TTF treatment, the Ki-67 labeling index was higher on infratentorial than on supratentorial in the autopsy specimens, suggesting the anti-tumor effect of TTF for the supratentorial lesion.

RESULTS
High proliferative activity of infratentrial lesion was suggested as a typical form of progression for TTF treatment.
SURG-57. FLUORESCENCE LIFETIME IMAGING (FLIM) PROVIDES HIGHLY ACCURATE, DYE-FREE TUMOR MARGIN DETECTION DURING GLIOMA RESECTIONS
Authors: Bloch Orin , Anbunesan Silvia , Alfonso-Garcia Alba , Lee Han , Riestenberg Robert , Marcu Laura 
Published: November 2024

Abstract

INTRODUCTION
Fluorescence guided tumor margin detection is an important tool to enhance the extent of resection for gliomas. Existing dyes, such as 5-ALA, require planned administration, surgical resection in dark conditions, and are only effective for high-grade tumors. We have developed a novel laser scanning probe to assess tissue autofluorescence decay (lifetime) which allows tumor margin detection without exogenous dyes and under normal room light conditions. This technology has been optimized for margin detection in low-grade and high-grade gliomas.

METHODS
Patients undergoing craniotomy for resection of gliomas were enrolled. During resection of the final tumor margin, multiple 1x1 mm regions were scanned with FLIm and biopsied for evaluation by a neuropathologist. FLIm data and ground truth pathology were processed by a machine-learning algorithm to develop classifiers for the FLIm data. Classifiers were then applied to the full data set to determine the accuracy of FLIm predictions.

RESULTS
12 patients with non-enhancing (LGG) and 25 patients with enhancing (HGG) tumors were enrolled, with a total of 228 biopsies obtained. For LGG, sensitivity of FLIm for detection of residual tumor was 0.89 (95% CI 0.8-0.98) with a specificity of 0.92 (95% CI 0.86-0.97), resulting in a positive predictive value of 0.76 and negative predictive value of 0.96 with an overall accuracy of 0.91. For HGG, sensitivity of FLIm for detection of residual tumor was 0.92 (95% CI 0.84-1.0) with a specificity of 0.95 (95% CI 0.91-0.99), resulting in a positive predictive value of 0.90 and negative predictive value of 0.96 with an overall accuracy of 0.94, exceeding reported values for 5-ALA.

CONCLUSION
FLIm can distinguish between residual low and high-grade glioma and normal brain at resection margins with very high sensitivity and specificity. This quantitative technology does not require administration of exogenous dyes and can be used under normal room light illumination.
TMET-01. LIPID METABOLIC PROGRAMS DEFINE GLIOMA STATE IDENTITY, PLASTICITY AND DEPENDENCIES
Authors: Minami Jenna , Bayley Nicholas , Tse Christopher , Andrasz Cassidy , Cadet Dimitri , Salinas Jennifer , Yan Weihong , Borujerdpur Amir , Liau Linda , Cloughesy Timothy , Williams Kevin , Bensinger Steven , Bhaduri Aparna , Graeber Thomas , Nathanson David 
Published: November 2024

Abstract
Gliomas are lethal malignancies comprised of heterogeneous and dynamic subpopulations of cell states resembling normal neurodevelopmental cell types (radial glia (RG), oligodendrocyte progenitor cell (OPC), neuron progenitor cell (NPC), neuron, etc). While both intrinsic (genetics) and extrinsic (brain environment) cues are coupled to glioma state identity, the functional programs governing glioma cell state and plasticity are unknown. Here we performed a multi-omic interrogation of a large library (n=392) of glioma patient tumors, in vivo orthotopic xenografts and in vitro gliomasphere cultures. Comparisons of matched glioma samples across environments revealed the non-native in vitro environment constrains glioma state diversity specifically enriching for stem-like glioma cell states (RG, immune, vascular). This enrichment was linked to lipid metabolic flexibility, enabling tumors enriched for stem-like states to adapt to various tumor microenvironments. By contrast, “lineage-committed” cell states (OPC, NPC, and neuron) demonstrate restricted lipid metabolism, consequently having a dependence on lipid scavenging from the brain microenvironment for survival. These results connect intra-tumoral heterogeneity and plasticity of glioma to lipid metabolism, leveraging the functional diversity of cellular states to reveal potential therapeutic opportunities.
TMET-18. MANNOSE INHIBITS GLIOMA CELL PROLIFERATION AND POTENTIATES TEMOZOLOMIDE EFFICACY
Authors: Cho HyeJoung , Yoon Yeo Jun , Hoon Roh Tae , Kang Seok-Gu 
Published: November 2024

Abstract
Gliomas are among the most aggressive types of brain tumors, often displaying resistance to standard therapies such as temozolomide (TMZ). Recent research suggests that metabolic modulation may influence tumor growth and therapeutic response. This study explores the effects of mannose, a monosaccharide, on glioma cell growth and its potential to enhance the efficacy of TMZ. In vitro experiments were conducted to evaluate the impact of mannose and its combination with TMZ on glioma cells. Cell viability assays, ATP measurements, and flow cytometry (FACS) analysis were performed to assess cell cycle and apoptosis post-treatment with various monosaccharides, including mannose. The synergistic effects of the combined treatment with mannose and TMZ on cell viability were evaluated using Bliss score analysis and FACS. The impact on cancer stem cell characteristics was investigated through neurosphere formation assays, while tumor invasiveness was assessed using 3D invasion assays. Expression of stemness and invasion markers was analyzed by western blot. Differentially expressed gene (DEG) analysis was conducted to assess changes in gene expression related to stemness and invasiveness. Mannose treatment significantly reduced glioma cell viability and ATP levels, indicating decreased metabolic activity. Combined treatment with mannose and TMZ demonstrated a synergistic effect, enhancing cell death compared to either treatment alone, as evidenced by Bliss score and FACS analysis. Co-treatment reduced neurosphere formation and 3D invasion capabilities, with western blot results showing downregulation of stemness and invasion markers. DEG analysis revealed significant changes in gene expression related to stemness and invasiveness with the combined treatment. Mannose significantly impairs glioma cell growth and enhances the therapeutic efficacy of TMZ in vitro. Combining mannose with standard chemotherapy offers a promising strategy for improving glioma treatment outcomes. Further investigation in clinical settings is warranted to validate these findings.
TMET-30. ONCOLYTIC HSV REWIRES METABOLISM TO PROMOTE ANTITUMOR IMMUNITY THROUGH REDUCTIVE CARBOXYLATION AND FERROPTOSIS
Authors: Sahu Upasana , Mullarkey Matthew P , Murphy Sara , Diaz Miguel , Park Junhyoung , Kamal Abu Hena Mustafa , Kaiparettu Benny Abraham , Lee Tae Jin , Anderson Joshua Charles , Sharma Ashok , Putluri Nagireddy , Wenzel Pamela , Wiley Christopher , Markert James M , Kaur Balveen 
Published: November 2024

Abstract
Cancer cells autonomously rewire metabolism to meet increased bioenergetic demands. Oncolytic HSVs (oHSVs) are attenuated Herpes simplex type 1 derived viruses that lyse tumor cells releasing damage-associated molecules triggering antitumor immunity. Currently one oHSV-1 derived virus is approved for melanoma treatment in the USA and another for recurrent GBM in Japan. While several other viruses are being evaluated in clinical trials for safety and efficacy, an understanding of the impact of oHSV therapy on cancer cell metabolism is largely unexplored. A detailed understanding of how oHSV impact tumor cell metabolism and oxidative stress is important to understand the unique susceptibilities that can further be exploited to improve the therapeutic index. Here, we analyzed transcriptomic changes in tumor biopsies of recurrent high-grade glioma patients treated with oHSV. RNA-seq data obtained from pre- and post-G207 treated biopsies from phase-Ib study patients (NCT00028158) revealed enrichment in pathways related to citric acid cycle, oxidative phosphorylation, and glutamate metabolism. We confirmed these changes by RNA sequencing of oHSV-infected patient derived GBM cells. Mechanistically, oHSV hijacked cellular glucose metabolism to increase oxidative phosphorylation and modulated cellular glutamine metabolism towards reductive carboxylation and reduced free glutathione, collectively contributing to increased ROS generation. Kinome profiling revealed PKC activation upon treatment with oHSV. Increased ROS combined with reduced glutathione, and PKC activation promoted ferroptotic cell death characterized by increased lipid peroxidation and smaller, ruptured mitochondria, and contributed to immunotherapy by this treatment. IDH mutant tumors that block reductive carboxylation were resistant to oHSV-induced ferroptotic cell death and did not benefit from oHSV-induced antitumor benefit. Together, this study presents avenues to enhance antitumor immunity by oHSV therapy.
TMET-39. DUAL TARGETING OF MAP KINASE SIGNALING AND METABOLISM IS A THERAPEUTIC VULNERABILITY IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Gatesman Taylor , Casillo Stephanie , Chilukuri Akanksha , Varadharajan Srinidhi , Premkumar Daniel , Jane Esther , Johnson Brenden , Plute Tritan , Halbert Matthew , Cruz Andrea , Abel Taylor , Mack Stephen , Pollack Ian , Agnihotri Sameer 
Published: November 2024

Abstract
Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. However, there remains a knowledge gap in identifying effectors of ERK signaling and their roles in DMG-H3K27a. Leveraging several patient multi-omic datasets, we identified a unique relationship between ERK5 and brain tumor glycolysis. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a, where ERK5 knockdown leads to decreases in glycolysis and increases in mitochondrial metabolism. We demonstrate through loss of function and overexpression studies that ERK5 mediates glycolysis through regulation of glycolytic enzyme Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3). PFKFB3 is a protein that catalyzes the synthesis or degradation of fructose-2,6-bisphosphate (F2,6BP). Furthermore, we establish a novel mechanism, in which ERK5 mediates PFKFB3 expression via activation of MEF2A, an oncogenic transcription factor. DMG-H3K27a cells are sensitive to the loss or inhibition of PFKFB3 both in vitro and in orthotopic mouse models. However, monotherapy is ineffective in heterogenous diseases such as gliomas, including DMG-H3K27a. To combat this, we show multi-targeted therapy against the ERK5-PFKFB3 axis is synergistic in vitro and in vivo. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma. Moreover, we have identified resistance to our dual therapy using several systems biology approaches, which we are currently investigating and validating. Collectively, our study defines a novel, targetable axis in DMG-H3K27a and highlights the importance of tumor cell metabolism in defining therapeutic vulnerabilities.
TMET-40. UPREGULATION OF URIDINE SALVAGE IN MESENCHYMAL GLIOBLASTOMA STEM-LIKE CELLS
Authors: Baljinnyam Tuvshintugs , Sowers Mark , Chang-gu Bruce , Tang Hui , Herring Jason , Zhang Kangling , Sowers Lawrence 
Published: November 2024

Abstract
Glioblastoma is a heterogenous tumor comprised of multiple molecular subtypes of cancer cells and cancer stem-like cells. Of particular importance are the cancer stem-like cell niche population as they are believed to be more resistant to existing therapies and re-seed the tumor following initial response to standard-of-care treatment. To better understand glioblastoma stem-like cells we completed an untargeted proteomic analysisof 35 patient derived glioblastoma stem cell lines. This system driven analysis revealed an increase in several important proteins, in the mesenchymal subtype, involved in the uridine salvage pathway. A subset of these proteins, including ecto-5’-nucleotidase (NT5E/CD73), uridine phosphorylase (UPP1), phosphoglucomutase-2-like-1 (PGM2L1), nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide N-methyltransferase (NNMT), suggest an augmented pathway for utilization of UMP and uridine as a fuel source and to replenish NAD+. Uridine and UMP are present in human serum and are enriched in the tumor microenvironment providing a sustainable resource to resupply the tumor. The upregulation of this pathway was validated in established cell lines and orthogonal patient-derived xenograft cell lines not included in the proteomics study. Further work is underway to selectively inhibit or exploit this pathway with small molecule inhibitors.
TMIC-09. DENDRITIC CELL DYSFUNCTION RESTRICTS TUMOR ANTIGEN SPREADING IN ADOPTIVE CELLULAR TRANSFER THERAPY-ESCAPED GLIOMAS: IMPLICATIONS FOR TUMOR IMMUNE EVASION
Authors: Jin Dan 
Published: November 2024

Abstract
Dendritic cells (DCs) play a pivotal role in initiating anti-tumor immune responses. Our group has developed an adoptive cellular transfer therapy (ACT) that significantly increases the infiltration of DCs and T cells into tumors, markedly enhancing survival in murine brain tumor models. However, tumors develop mechanisms to restrict the immune surveillance and the efficacy of immunotherapy, leading to tumor escape. In this study, we identified a mechanism involving DC dysfunction in ACT-escaped brain tumors. The finding that DCs are enriched after ACT treatment prompts an investigation into whether DC function is impaired in ACT-escaped tumors. Our results showed that DCs from both primary and ACT-escaped tumors were dysfunctional in their ability to activate T cells when co-cultured with tumor-reactive T cells or OT1 T cells. RNA-seq data revealed that, compared to primary tumor DCs, ACT-escaped tumor DCs exhibited a more pronounced reduction in conventional DC markers and antigen-presenting genes, alongside increased tolerance markers. Gene set enrichment analysis indicated that epithelial-mesenchymal transition (EMT) and hypoxia pathways were significantly enriched in ACT-escaped tumor DCs, suggesting divergent DC dysfunction mechanisms in primary versus escaped tumors. The anti-tumor role of DCs is primarily exerted through the activation of tumor-reactive T cells. Therefore, we assessed the cytotoxicity and exhaustion status of T cells in tumors. Surprisingly, we found that T cells from ACT-escaped tumors exhibited significantly higher levels of cytotoxicity and lower levels of T cell exhaustion compared to primary tumors. This suggests a T cell exhaustion-independent mechanism in ACT-escaped tumors. We further demonstrated that T cells in ACT-escaped tumor are mainly sourced from the adoptive transferred T cells, which recognize primary tumor antigens but not escaped tumor antigens. These results suggest that a combined mechanism of tumor antigen shifting and impaired DC function leads to a failure of antigen spreading and tumor eradication.