bluuebunny/crossref_metadata_2025_split huggingface dataset:
RTID-02. PERSONALIZED PEPTIDE VACCINATION AMONG 173 PATIENTS WITH GLIOBLASTOMA
Authors: Latzer Pauline , Zelba Henning , Battke Florian , Reinhardt Annekathrin , Shao Borong , Biskup Saskia 
Published: November 2024

Abstract
Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. GBM tumors from 173 patients were analyzed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoepitopes. In agreement with their treating physician, patients added a personalized peptide vaccine to their treatment as an individual healing attempt. Patients were monitored from October 2015 until August 2023. We retrospectively evaluated their clinical courses and the results of their immune monitoring data. Among all patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis was 31.9 months (95% CI: 25.0-36.5). Adverse events were infrequent and were predominantly grade 1 or 2. An immune response to at least one of the vaccinated peptides was detected in blood samples of 87 of 97 (90%) monitored patients. T-cell responses to vaccinated neoepitope peptides were durable in most patients. Significantly prolonged survival was observed for patients with multiple vaccine-induced immune responses (53 months) compared to those with no/low induced responses (27 months; P=0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients. This is the largest real-world observation involving GBM patients safely treated with a personalized peptide vaccine to date. This real-world observation will be translated into a clinical trial to evaluate the specific contribution of the neoantigen vaccine.
RTID-05. STUDY PROTOCOL: A MULTICENTER, INTERNATIONAL RANDOMIZED CONFIRMATORY TRIAL: LOW-ENERGY X-RAY INTRAOPERATIVE RADIATION THERAPY (LEX-IORT) VS. ADJUVANT FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) IN THE MANAGEMENT OF BRAIN METASTASES (LEXIMATE)
Authors: Diehl Christian D , Acker Güliz , Brehmer Stefanie , Ganslandt Oliver , Giordano Frank A , Hamed Motaz , Kahl Henning , Münter Marc , Layer Julian P , Sarria Gustavo R , Schneider Matthias , Shiban Ehab , Wagner Arthur , Meyer Bernhard , Combs Stephanie E 
Published: November 2024

Abstract

BACKGROUND
Fractionated stereotactic radiotherapy to the resection cavity boosts local control of resected brain metastases significantly. However, start of systemic tumor-directed treatment may be protracted and in-hospital times prolonged. Lately, lex-ioRT of BM has been described as a safe and effective one stop-shop treatment modality with a 1-year local control rate of up to 98% while potentially improving patient convenience. Study Design: The LEXIMATE-trial is a multicenter, international, randomized open-label confirmatory trial comparing lex-IORT with FSRT of resected BM. In the experimental arm, INTRABEAM (Carl Zeiss Meditec AG) is used to deliver IORT by application of 50-kV photons at a standard dose of 30 Gy prescribed to the applicator surface. Standard linear accelerator or Gamma Knife based FSRT (3-7 fractions) to the surgical bed is used in the control arm. The primary endpoint is the cumulative incidence of local recurrences (as per RANO-BM) considering death without prior local recurrence as competing event. Inclusion criteria include histologically confirmed BM with indication for resection according to EANO-ESMO/ASCO-SNO-ASTRO guidelines, ≤5 other brain lesions compatible with BM and amenable to radiosurgery and history of solid cancer or CT scan suggestive for localized or metastasized solid cancer (except germ cell tumors, lymphoma, small-cell lung cancer). The resection cavity must be &lt;5cm in size, IORT doses to brainstem or optical tract may not exceed 8 Gy. Study design: Randomized, open-label, non-inferiority. Sample size: 70 patients per group to show a non-inferiority of the experimental therapy compared to the control therapy with a power of approximately 80%.

DISCUSSION
The best radio-oncologic procedure for resected BM remains under debate. The LEXIMATE-trial offers an opportunity to provide more solid prospective data on effectiveness, safety and patient comfort both for established and new RT techniques.
TMET-03. ONCOGENIC STAT3 PROMOTES TUMOR GROWTH VIA STIMULATION THE SCAP- AND SREBP-1-REGULATED LIPOGENIC PATHWAY
Authors: Fan Yunzhou , Zhang Rui , Wang Chao , Pan Meixia , Geng Feng , Zhong Yaogang , Su Huali , Kou Yongjun , Mrinalini Rajeev , Mo Xiaokui , Han Xianlin , Lefai Etienne , Guo Deliang 
Published: November 2024

Abstract
Augmented lipogenesis is a hallmark of cancer. In addition, signal transducer and activator of transcription 3 (STAT3) is aberrantly activated and associated with poor prognosis in multiple cancers. Whether oncogenic STAT3 has an intrinsic and causal link to lipogenesis in cancer remains unclear. Here, we show that inhibition of STAT3 significantly alters the lipid profile of tumor cells, including free fatty acids and derived membrane structural phospholipids (phosphatidic acid, phosphatidylinositol, phosphatidylserine and sphingomyelin), this change results in cell death which could be rescued by lipids (oleic acid and palmitoleic acid) supplementation, while suppressing the gene and protein expression of major mediators of the lipogenic pathway including sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-1, fatty acid synthase and stearoyl-CoA desaturase 1. Furthermore, we show that STAT3 binds the promoter of SCAP, SREBP-1a and SREBP-1c, to promote their transcription in tumor cells. Finally, targeting STAT3 in a xenograft mouse model blocked glioblastoma growth and lipogenic enzyme expression. Our study reveals a novel regulatory pathway of STAT3-SCAP/SREBP-1 involved in tumor growth in vitro and in vivo, connecting STAT3 signaling with SCAP- and SREBP-1-mediated lipogenesis.
TMET-10. TARGETING PGM3 TO INHIBIT HEXOSAMINE PRODUCTION IS AN EFFECTIVE APPROACH TO TREAT GLIOBLASTOMA
Authors: Su Huali , Zhong Yaogang , Geng Feng , Fan Yunzhou , Kou Yongjun , Chiang Cheng-yao , Mo Xiaokui , Magaki Shino , Cloughesy Timothy F , Lefai Etienne , Yong William H , Chakravarti Arnab , Guo Deliang 
Published: November 2024

Abstract
Hexosamine biosynthesis pathway (HBP) mediated by a series of enzymes is highly upregulated in many cancers to promote the glycosylation of proteins and lipids, while which enzyme in this pathway is better to serve as anti-tumor target is unclear. Here, we found targeting GFAT1, the initial and rate-limiting enzyme in HBP, fails to inhibit the growth of glioblastoma (GBM), the most lethal brain tumor, due to this cancer dramatically elevating NAGK-mediated hexosamine salvage pathway. In contrast, targeting PGM3, the latter enzyme in HBP, blocks both de novo hexosamine synthesis and salvage pathways, effectively inhibiting GBM growth. We further identified HBP enzymes are upregulated by SREBP-1, a key lipogenic transcriptional factor. In turn, this upregulation promotes SREBP-1 activation to stimulate lipogenesis via stabilization of its key transporter SCAP by N-glycosylation modification. Together, our study uncovered a previously unrecognized HBP-SCAP-SREBP-1 feedforward loop and demonstrated targeting PGM3 is an effective approach to treat GBM.
TMET-12. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN GLIOMAS
Authors: Ohba Shigeo , Teranishi Takao , Hirayama Akiyoshi , Hitachi Keisuke , Yamaguchi Hisateru , Natsumeda Manabu , Tateishi Kensuke , Pieper Russell , Hirose Yuichi 
Published: November 2024

Abstract
Isocitrate dehydrogenase (IDH) wild-type gliomas and IDH mutant gliomas are similar in histologic appearance but differ in their genetic and metabolic backgrounds. This study aimed to reveal the difference in metabolites between IDH-wildtype glioma and IDH-mutant glioma, and to find the effective treatment according to the status of IDH in gliomas. Two artificial cell lines made from human astrocyte were used: NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant). Using capillary electrophoresis- and ion chromatography–coupled mass spectrometry, the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells, whereas the amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells was lower than NHAE6E7hTERTRas cells. L-asparaginase, which converts asparagine into aspartate, was more effective in NHAE6E7hTERTRas cells than NHAE6E7hTERTIDHmut cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect, which meant that the antitumor effect was at least partially due to the L-asparaginase-induced autophagy. Pharmacological or genetical inhibition of GLUD1 which converts glutamate to 2-oxoglutarate, suppressed proliferation of the cells by inducing ROS and apoptosis in NHAE6E7hTERTIDHmut cells. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells, revealing that cytotoxicity by GLUD1 inhibitor was at least partially due to the inhibitor-induced ROS. The experiments using mutant IDH1 overexpressed glioma cell line showed similar sensitivity to GLUD1 inhibitor to NHAE6E7hTERTIDHmut, which suggested that the difference of sensitivity to GLUD1 inhibitor was due to the status of mutant IDH. In vivo experiments, L-asparaginase suppressed the growth of xenografted glioma cells without mutant IDH, whereas GLUD1 inhibitor inhibited the proliferation of xenografted glioma cells with overexpressed mutant IDH1. In conclusion, L-asparaginase and Glud1 inhibitor will be new therapeutic option for IDH-wildtype glioma and IDH-mutant glioma, respectively.
TMET-13. SPATIAL METABOLOMIC CHANGES OF NUCLEOTIDE IN THE BRAINS OF ORTHOTOPIC MOUSE GLIOMA MODEL AFTER BORON NEUTRON CAPTURE THERAPY (BNCT)
Authors: Kondo Natsuko , Kobayashi Nao , Sakurai Yoshinori , Suzuki MInoru , Yamaguchi Shinichi , Ikegawa Masaya 
Published: November 2024

Abstract
Glioblastoma is the most lethal primary brain tumor. Boron Neutron Capture Therapy (BNCT) is a tumor-selective particle radiation therapy, in which high-LET α-particles and recoil 7Li are produced by the capture reaction between 10B and thermal neutrons and it has extended the prognosis of glioblastomas [Kawabata S, et al., Neuro-Oncology Advances 3(1), 1–9, 2021]. Augmented synthesis and use of nucleotide triphosphates is critical and universal metabolic dependency of tumor cells [Mullen, N.J., Singh, P.K. Nat Rev Cancer 23, 275–294 (2023)]. However, the effects of BNCT on metabolism of purine and pyrimidine in brain tumors and the surrounding normal brain are unknown. We spatially investigated metabolomic change in brains of orthotopic mouse glioma model, before and 2, 7, and 14 days after BNCT using mass spectrometry imaging (MSI). By separating tumor and non-tumor areas and performing Partial Least Squares Regression calculations, we have successfully visualized tumor-specific metabolites including adenine (ATP, ADP) and uridine (UTP, UDP-glucose, UDP-GlcNAc) with MSI. Of note, the signal of top-scored tumor specific metabolite, UDP-GlcNAc dramatically decreased and disappeared as the tumor regressed. Furthermore, the signal of ADP which was supposed to be released from tumor, colocalized with invading tumors along with corpus callosum. The value of adenylate energy charge, ([ATP]+0.5[ADP]/[ATP]+[ADP]+[AMP]) in the surrounding normal brain of the untreated tumor-bearing mouse increased up to 0.37 and decreased gradually down to 0.32 with BNCT, approaching to the value of normal control mouse brain, 0.27. These metabolomic changes reflected the tumor-killing effect and restoration of energy charge of surrounding normal brain by BNCT and have potential significance for development of biomarker or diagnosis.
TMET-14. ENOLASE 2 IS A UNIQUE METABOLIC VULNERABILITY INDUCED BY THE 1P19Q CODELETION IN OLIGODENDROGLIOMAS
Authors: Udutha Suresh , Batsios Georgios , Gillespie Anne Marie , Viswanath Pavithra 
Published: November 2024

Abstract
Gliomas are devastating primary brain tumors in adults. The presence of an isocitrate dehydrogenase mutation combined with a chromosomal 1p/19q codeletion discriminates oligodendrogliomas from astrocytomas. The goal of this study was to leverage metabolic vulnerabilities induced by the 1p/19q codeletion for oligodendroglioma therapy. The 1p19q codeletion results in loss of enolase 1 (ENO1), which converts 2-phosphoglycerate to phosphoenolpyruvate during glycolysis. Here, we show that enolase 2 (ENO2) is upregulated in patient-derived oligodendroglioma (SF10417, BT88, BT54) models relative to astrocytoma (BT142, SF10602) and normal human astrocytes. ENO2 is also elevated in oligodendroglioma patient biopsies relative to astrocytoma or gliosis. Mechanistic studies indicate that inhibiting MEK1 or ERK1 abrogates ENO2 expression, suggesting that the MAPK pathway upregulates ENO2 in oligodendrogliomas. Next, we examined the therapeutic potential of targeting ENO2 in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited the viability of SF10417 and BT88 cells with IC50 values of ~50 nM. In contrast, the IC50 for BT142 and SF10602 astrocytoma cells was ~5-8 uM, highlighting the exquisite dependence of oligodendrogliomas on ENO2. However, ENO2 inhibition did not lead to cytotoxicity in patient-derived oligodendroglioma cells or intracranial tumor xenografts. To assess the metabolic consequences of ENO2 inhibition and identify potential compensatory alterations, we traced [U-13C]-glucose metabolism in vivo in mice bearing intracranial SF10417 tumors. Although POMHEX abrogated glycolytic metabolism downstream of 2-phosphoglycerate, it shunted glucose towards biosynthesis of serine, glycine, methionine and purine nucleotides, an effect that was driven by phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for serine biosynthesis. Importantly, the novel PHGDH inhibitor PHGDH-D8 was synthetically lethal in combination with POMHEX in oligodendroglioma cells and the combination induced apoptosis in mice bearing intracranial SF10417 tumors. Collectively, we exploit a mechanistic understanding of metabolic vulnerabilities induced by the 1p19q codeletion to identify combined inhibition of ENO2 and PHGDH as a novel therapeutic opportunity for oligodendrogliomas.
TMET-25. WILD-TYPE IDH1 INHIBITS FERROPTOSIS IN GLIOBLASTOMA
Authors: Dunterman Madeline , Korimerla Navyateja , Murnan Kevin , Tommasini-Ghelfi Serena , Wahl Daniel , Stegh Alexander 
Published: November 2024

Abstract
De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that glioblastoma (GBM) up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high GBM) that, through oxidative decarboxylation of isocitrate, generates large quantities of alpha-ketoglutarate and cytosolic NADPH. We demonstrated that RNAi-mediated knockdown of wt-IDH1, alone and in combination with RT, slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Here, we demonstrate that wt-IDH1high GBM produce excess NADPH, which is a rate-limiting reductant that drives de novo fatty acid biosynthesis. Isotope tracer and liquid chromatography-based lipidomic studies indicate that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs), promotes the incorporation of monounsaturated, and reduces the abundance of oxidizable polyunsaturated (PUFA) phospholipids in the cell membrane. Conversely, the genetic ablation of wt-IDH1 or the pharmacologic inhibition of wt-IDH1 in tumor cells, using a brain-penetrant wt-IDH1-specific small molecule, revealed a significant increase in PUFA-containing lipid species harboring oxidized arachidonic tails. Of note, two lipid species, (PE16:0_20:4) and (PE18:0_22:4), previously reported to act as substrates for 15-lipoxygenase (15-LOX) - a key enzyme that facilitates lipid peroxidation - are enriched in tumor cells with wt-IDH1 compromise. Further, we found that the enhanced NADPH production in wt-IDH1high GBM, together with heightened biosynthesis of carbon precursors required for glutathione biosynthesis, increased levels of reduced glutathione (GSH), activate the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, which scavenges PUFA-containing lipid peroxides, known executioners of ferroptosis. These findings support elevated wt-IDH1 expression, the ensuing effect on the tumor lipidome, redox homeostasis, and protection against lipid peroxidation as contributors to GBM tumor growth and therapy resistance and point to the inhibition of wt-IDH1 as a ferroptosis-inducing strategy for the treatment of GBM.
TMET-27. MACHINE LEARNING-BASED IDENTIFICATION OF METABOLIC FLUXES IN PATIENT BRAIN TUMORS
Authors: Meghdadi Baharan , Mittal Anjali , Scott Andrew , Liang Ningning , Palavalasa Sravya , Achreja Abhinav , Kothari Alexandra O’Brien Ayesha , Zhou Weihua , Xu Jie , Lin Angelica , Wilder-Romans Kari , Edwards Donna , Wu Zhe , Feng Jiane , Andren Anthony , Zhang Li , Tarnal Vijay , Redic Kimberly , Qi Nathan , Lawrence Theodore , Lyssiotis Costas , Al-Holou Wajd , Wahl Daniel , Nagrath Deepak 
Published: November 2024

Abstract
Personalized oncology aims to match effective treatments for individual cancer patients based on the biology of an individual tumor. This approach is not possible for metabolic therapies due to our inability to quantify metabolic activity in patient tumors, even when patients are infused with 13C-glucose. We overcame this challenge by generating training data with a prior knowledge of 13C-glucose infused patient data and implementing a machine learning model to predict fluxes. We trained a convolutional neural network (CNN) to predict flux ratios. To validate our model, we compared predicted flux ratios to the experimental 13C-glucose-infused mouse models to predict treatment responses for: (1) pharmacologic inhibition of de novo GMP synthesis and (2) environmental serine restriction. Our GMP synthesis model predicted elevated GMP synthesis in GBM compared to cortex in a mouse model and discriminated between sources of GMP synthesis in patients. These findings allow prediction of potential responders to mycophenolate mofetil (MMF), which inhibits de novo but not salvage GMP synthesis. Furthermore, we previously showed that circulating serine uptake is higher in GBM than normal cortex, and a serine- and glycine-restricted diet slows tumor growth in mice. While de novo serine synthesis, circulating and microenvironmental-derived serine could account for serine sources in GBM, our model can distinguish between serine sources in patients, hence potentially predict response to dietary serine depletion. Thus, we have shown that our model may identify patients who will benefit from MMF treatment or a serine- and glycine-restricted diet, potentially enabling administration of highly effective personalized metabolic treatments for GBM patients.
TMIC-15. GUT MICROBIOTA CONTROLS NEUROFIBROMATOSIS-1 (NF1) OPTIC GLIOMA GROWTH THROUGH IMMUNE CIRCUIT MODULATION
Authors: Chatterjee Jit , Qi Xuanhe , Ouyang Megan , Mu Rui , Li Xuanwei , Bozeman Stephanie L , Eligator Talia , Schriefer Lawrence A , Rodgers Rachel , Baldridge Megan T , Gutmann David H 
Published: November 2024

Abstract
Changes in the gut microbiome can have profound effects on the nervous system through modulation of T cell and microglia function. Since our prior studies demonstrated that T cells and microglia positively regulate low-grade glioma growth through the establishment of T cell-microglia immune circuit, we sought to explore the impact of changes in the gut microbiota on tumor biology. For these studies, genetically engineered Neurofibromatosis type 1 (NF1) optic glioma (Nf1-OPG) mice were raised in a germ-free environment or treated with antibiotics to deplete gut bacteria. First, we demonstrated that Nf1-OPG mice raised in a germ-free (gnotobiotic) environment or treated with specific antibiotics lacked optic gliomas and had improved OPG-induced retinal pathology (increased retinal nerve fiber layer thickness). Second, germ-free and antibiotic-treated Nf1-OPG mice gavaged with fecal microbiota from Nf1-OPG mice raised in a standard barrier facility restored optic glioma growth. Third, we showed that both germ-free and antibiotic-treated Nf1-OPG mice exhibited reduced intra-tumoral CD8+ T cell content resulting from decreased microglia chemokine production. Fourth, we discovered a gut-brain paracrine axis whose interruption reduced optic glioma growth and attenuated retinal nerve fiber layer thinning. Collectively, these findings establish a mechanistic relationship between the gut microbiota and brain tumor growth relevant to potential therapeutic interventions for pediatric low-grade gliomas.
TMIC-73. SEX DIFFERENCES IN INTERFERON-GAMMA RESPONSES IN GLIOMA MICROENVIRONMENT
Authors: Leu Jia-Shiun , Tran Han Nhat , Ismail Taha S , Yun Kyuson 
Published: November 2024

Abstract
IFNγ is a cytokine with both pro- and anti-tumorigenic effects and its role in glioma immunotherapy resistance is not well understood. In the tumor microenvironment, T and NK cells produce IFNγ, which affects cellular phenotypes in most of the cancer and stromal cells since IFNγ receptor is ubiquitously expressed. IFNγ induces expression of molecules that confer resistance to immunotherapies, such as PDL1, PDL2, IDO1, and iNOS. The goal of this study is to elucidate cell type-specific responses to IFNγ in immune competent glioma models we developed that are resistant to immunotherapy. We intracranially injected male and female murine glioma cells into B6 and Ifng-/- honst mice to measure overall survival and perform immune phenotyping and single cell RNA-sequencing analyses. Ifnγ-/- hosts exhibited a shorter survival, and the proportion of GBM cells is higher in Ifng-/- hosts compared to wild type, indicating that the net effect of IFNγ signaling in glioma is anti-tumorigenic. In a recent study, we published that IFNγ-response pathway is enriched in the mesenchymal-like (MES-like) subtype of human GBM cells, compared to neutral-progenitor-like (NPC-like) and oligodendrocyte-progenitor-like (OPC-like) cells (Abdelfattah et al., 2022). To test our hypothesis that IFNγ signaling induces MES transition in glioma cells in vivo, we compared fractions of glioma cell subtypes in wildtype and Ifng-/- male and female hosts. In female Ifng-/- mice, MES-like GBM cell fraction was reduced while OPC-like fraction was increased, supporting our hypothesis. However, there was no difference in male hosts. Furthermore, gliomas grown in female B6 hosts showed higher infiltration of immune cells (CD45+), lymphocytes (CD3+) and fewer resident microglia cells (CD11b+CD45int), compared with Ifng-/- female hosts. In contrast, no significant difference in immune cell infiltration was observed between B6 vs Ifng-/- males. These results suggest an unanticipated and complex context-dependent role of IFNγ signaling in GBM, which include sex differences in its role in immune cell recruitment and MES transition in glioma cells.