bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMET-05. INCREASING GLUTAMINE UPTAKE-LIPOGENESIS AXIS PROMOTES TUMOR RESISTANCE TO LYSOSOME INHIBITION
Authors: Zhong Yaogang , Geng Feng , Mazik Logan , Yin Xinmin , Becker Aline Paixao , Mohammed Shabber , Su Huali , Xing Enming , Kou Yongjun , Chiang Chengyao , Fan Yunzhou , Li Pui-Kai , Mo Xiaokui , Lefai Etienne , He Liqing , Cheng Xiaolin , Zhang Xiang , Chakravarti Arnab , Guo Deliang 
Published: November 2024

Abstract
An effective therapy for glioblastoma (GBM), the most lethal brain tumor, is lacking1-11. Several antipsychotic drugs, including pimozide, have recently been shown to have anti-GBM potential 12,13, but the development of tumor resistance diminishes their efficacy. Identifying the mechanisms for such resistance will help repurpose these brain-penetrant drugs for GBM therapy. Here, we found that pimozide inhibits cholesterol and fatty acids (FAs) release via lysosome-mediated lipid droplets (LDs) and lipoprotein hydrolysis, starving GBM cells of these essential building blocks. However, we identified that GBM cells become resistant to pimozide-based therapy due to an elevation of glutamine metabolism. Mechanistically, reductions in cholesterol and the promotion of signaling via sterol regulatory element-binding protein 1 (SREBP-1), a classical lipogenic transcription factor14, stimulate glutamine transporter ASCT2 expression, increasing glutamine uptake and consumption. Enhanced glutamine uptake leads to the release of ammonia that further stimulates SREBP-1 activation, thereby forming a feedforward loop to concurrently increase both glutamine metabolism and lipid synthesis, resulting in drug resistance. Pharmacological targeting of either ASCT2, or glutaminase (GLS) to limit glutaminolysis, abolishes this loop, and in combination with pimozide result in marked killing of GBM cells. Our study demonstrates that combinatorial targeting of glutamine metabolism and lysosomal function is a promising approach to treat GBM, which may be applicable to other aggressive cancers that are also addictive to glutamine and lipids.
TMET-16. GABA PRODUCTION INDUCED BY IMIPRIDONES IS A TARGETABLE AND IMAGEABLE METABOLIC ALTERATION IN DIFFUSE MIDLINE GLIOMAS
Authors: Batsios Georgios , Udutha Suresh , Taglang Celine , Gillespie Anne Marie , Lau Benison , Ji Sunjong , Phoenix Timothy , Mueller Sabine , Venneti Sriram , Koschmann Carl , Viswanath Pavithra 
Published: November 2024

Abstract
Diffuse midline gliomas (DMGs) are lethal brain tumors in children. The imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients, but efficacy as monotherapy is limited. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment. Here, using 1H-magnetic resonance spectroscopy (1H-MRS), which is a non-invasive method of quantifying metabolite pool sizes, we show that imipridones induce accumulation of gamma-aminobutyric acid (GABA) in patient-derived (BT245, SF8628) and syngeneic (26-B7, 26-C2) cells. Importantly, in vivo1H-MRS detects a significant increase in GABA within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic BT245, SF8628 or 26-B7 xenografts. Mechanistic studies show that imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, the enzyme that synthesizes GABA, and downregulates GABA transaminase, which degrades GABA, leading to GABA accumulation in DMG cells and orthotopic tumors. Since GABA is known to regulate oxidative stress signaling and since imipridones induce oxidative stress, we assessed whether GABA influences oxidative stress in DMG cells. Our studies indicate that GABA induces expression of superoxide dismutase (SOD1), which scavenges superoxide radicals and, thereby, curbs apoptosis induced by imipridones. The biological effects of GABA are mediated via signaling cascades triggered by GABA receptors and we find that GABA acts in an autocrine manner via the GABAB receptor to upregulate SOD1. Importantly, the clinically translatable GABAB receptor antagonist SGS742 and the SOD1 inhibitor ATN-224 exacerbate oxidative stress and synergistically induce apoptosis in combination with imipridones in DMG cells. Furthermore, SGS742 is brain-penetrant and potentiates ONC206-induced apoptosis in mice bearing orthotopic SF8628 xenografts in vivo. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for imaging drug-target engagement and for enhancing response to therapy. Clinical translation of our studies will enable precision therapy and imaging for DMG patients.
TMET-19. REWIRING OF CORTICAL GLUCOSE METABOLISM FUELS HUMAN BRAIN CANCER GROWTH
Authors: Scott Andrew , Mittal Anjali , Meghdadi Baharan , Palavalasa Sravya , Achreja Abhinav , O’Brien Alexandra , Kothari 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 , Fischer Joshua , Yang Ethan , Regan Michael , Stopka Sylwia , Baquer Gerard , Lawrence Theodore , Venneti Sriram , Agar Nathalie , Lyssiotis Costas , Al-Holou Wajd , Nagrath Deepak , Wahl Daniel 
Published: November 2024

Abstract
The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. In particular, we find that cortical tissue produces its own glucose-derived serine, whereas gliomas predominantly consume serine from the environment. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Combining dietary serine restriction with chemoradiation reduces brain tumor growth in mice, suggesting that such a dietary intervention could improve outcomes for patients with high grade glioma.
TMET-21. METABOLIC PROFILING OF MENINGIOMA REVEALS NOVEL SUBGROUP-SPECIFIC BIOLOGIC INSIGHTS AND OUTCOME DEPENDENCIES
Authors: Landry Alexander , Wang Justin , Liu Jeff , Patil Vikas , Zhang Wen-Jiang , Ellenbogen Yosef , Gui Chloe , Ajisebutu Andrew , Kislinger Thomas , Chen Eric , Nassiri Farshad , Zadeh Gelareh 
Published: November 2024

Abstract

BACKGROUND
Prior studies have elucidated the presence of four consensus molecular groups (MGs) of meningioma, with unique underlying biology and outcomes. The hyperactivation of metabolic pathways may be associated with tumour growth in so-called hypermetabolic (MG3) tumours, and there is a need to better understand the metabolic profiles of these tumours. This study is the first to study the global metabolon of meningioma in the context of modern molecular subgroups.

METHODS
We performed untargeted metabolic profiling of 53 meningiomas representing each MG and WHO grade. Prognostic biochemicals were identified using Cox regression and further investigated using RNA and protein-based pathway analyses. A larger cohort with available RNA sequencing (n=121) was used to further explore the prognostic influence of relevant pathways, and biochemicals of interest were validated on a subset of these samples (n=35) using targeted high performance liquid chromatography (HPLC).

RESULTS
Our untargeted approach identified 560 unique biochemicals for downstream analysis. The abundance of N6-trimethyllysine was associated with significantly earlier time to recurrence highly prognostic on our whole cohort (HR [95%CI] = 3.18 [1.45-26.23], p = 0.004) and within hypermetabolic (MG3) tumours (HR [95%CI] = 6.73 [1.72-6.97], p = 0.006); pyruvate was with worse outcomes in proliferative (MG4) tumours specifically (HR [95%CI] = 5.65 [1.073-29.71], p = 0.041). Analysis of implicated gene pathways demonstrated that upregulation of the oxidative phosphorylation pathway portends worse outcomes in the hypermetabolic subgroup but better outcomes in the proliferative subgroup. By contrast, upregulated lactate transporters were associated with worse outcomes in proliferative, but not hypermetabolic, meningiomas.

CONCLUSIONS
This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine and pyruvate in meningioma, offering increasingly granular outcome predictions using a widely accessible technique (HPLC). In addition, we demonstrated key differences in energy utilization between hypermetabolic and proliferative tumours suggesting fundamental differences in preferred energy utilization and reinforcing a need for subgroup-specific therapies.
TMET-26. TARGETING TRANSSULFURATION VIA SUPPRESSION OF THYROID HORMONE SIGNALING: A WINDOW OF OPPORTUNITY TRIAL OF METHIMAZOLE IN PATIENTS WITH PROGRESSIVE WHO GRADE 4 GLIOMAS (NCT05607407)
Authors: Peereboom David , Lathia Justin , Angelov Lilyana , Barnett G H , Cordova Christine , Dhawan Andrew , Hage Lea El , Grabowsky Matthew , Hufsey Rachel , Lobbous Mina , Malkin Mark , Mohammadi Alireza , Ponti Andras , Silver D J , Soni Pranay , Stevens Glen , Torres-Trejo Alejandro , Yang Kailin , Hine Christopher 
Published: November 2024

Abstract

BACKGROUND
Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits cancer cell behavior and growth in glioblastoma (GBM) models. H2S production capacity (HPC) is decreased in human GBM specimens compared to non-tumor controls. Thus, boosting HPC is a novel strategy for GBM treatment. Suppression of thyroid hormone signaling increases endogenous production of H2S. Hypothesis: hypothyroidism induced by methimazole will enhance the efficacy of chemotherapy in WHO grade 4 gliomas by increasing HPC within the tumor. Goal: proof of concept that methimazole, by reducing thyroid hormone signaling, can increase HPC in patients with WHO grade 4 gliomas (G4G).

METHODS
This window of opportunity trial evaluates safety, HPC in plasma and tumor, and efficacy of methimazole + chemotherapy in patients with progressive G4G.

MAIN OBJECTIVE
10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling. Patients planned for a clinically-indicated resection receive pre-op (5-7 days) and post-op methimazole with the addition of investigator’s choice of chemotherapy 1 month after starting post op methimazole. Patients receive methimazole + chemotherapy until progression. Pre- and post-op plasma and resected tumor tissue are assayed for HPC and proteins relevant to H2S production. Key eligibility: progressive G4G for whom a clinically-indicated resection is planned; normal thyroid function with no history of thyroid dysfunction. Patients may have received unlimited prior regimens including bevacizumab.

RESULTS
To date 12 patients (8 male) median age 56 years enrolled, 3 of whom are in pre-op phase. Relative to age/sex matched control, post-methimazole plasma at all time points tested but not tumor HPC increased (minimum increase 56%, p 0.041). No grade 3-5 toxicities or significant changes in thyroid function tests. PFS6 0 for first 6 patients.

CONCLUSIONS
Induction of subclinical hypothyroidism is feasible and safe in recurrent GBM with significant increases in plasma but not tumor HPC. The protocol is being modified to increase methimazole doses and allow earlier addition (10 days) of post-op chemotherapy.
TMET-29. TARGETING IDH1-MUTATED OLIGODENDROGLIOMA WITH ACID CERAMIDASE INHIBITORS
Authors: Muley Vilamu Helena , Dowdy Tyrone , Zaibaq Faris , Larion Mioara 
Published: November 2024

Abstract

BACKGROUND
Currently, an estimated 14,950 people lives with oligodendroglioma in the United States. Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut). Previously, we reported that in IDH1mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDHmut-specific glioma cell death.

METHODS
TCGA and CCGA data were used to explore the association between acid ceramidase (AC) gene expression and patient survival. CCK8 viability assays were carried out to measure the sensitivity of glioma cell lines to acid ceramidase inhibitors. Western blot and liquid chromatography-mass spectrometry analyses were performed for studying the mechanism of action of acid ceramidase inhibitors. The in vivo efficacy of the SABRAC drug, an irreversible inhibitor of AC, was evaluated in an orthotopic oligodendroglioma xenograft mice model using TS603 patient-derived oligodendroglioma cells. RESULTS. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and increases the survival of mice with IDH1mut oligodendroglioma. We demonstrated an IDH1mut-specific cytotoxicity of SABRAC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to a 30-fold increase in some ceramide levels and its derivatives from the salvage pathway.

CONCLUSIONS
We propose AC as a novel therapeutic target in oligodendroglioma with IDH1mut and we are conducting additional preclinical testing.
TMET-31. OXIDATIVE STRESS INDUCED PROTEIN AGGREGATION VIA GGCT PRODUCED PYROGLUTAMIC ACID IN DRUG RESISTANT GLIOBLASTOMA
Authors: Tiek Deanna , Song Xiao , Wu Runxin , Yu Xiaozhou , Iglesia Rebeca , Hu Bo , Cheng Shiyuan 
Published: November 2024

Abstract
Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (y)-glutamylcyclotranserase (GGCT), an enzyme in the y-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT – pyroglutamic acid – can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, as well as adjacent normal brain. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.
TMET-32. THE ROLE OF HOXC10 IN DRIVING GLIOBLASTOMA AGGRESSIVENESS
Authors: Vengoji Raghupathy , Perumalsamy Balaji , Thiraviyam Anand , Ogunleye Ayoola , Jain Maneesh , Ponnusamy Moorthy , Batra Surinder , Shonka Nicole 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive malignancy, with a tumor doubling time of just 49.6 days. Despite maximal safe surgical resection, radiation, and temozolomide, median survival is only 14.6 months. Homeobox gene, homeobox C10 (HOXC10), a transcription factor of the HOX10 family, is pivotal in neuronal development, upregulated in several cancers, including glioma, and correlates with poor survival.

METHODS
RNA sequencing analysis was done on our mouse glioma syngeneic cell lines. HOXC10 expression analysis was done on human and mouse GBM cell lines and tissues by immunoblotting and immunohistochemistry, respectively. HOXC10 and p16-/-silencing were done using 4 unique 29mer shRNA constructs in the GFP vector, respectively. Gene Ontology predicted HOXC10 functions. HOXC10 and pyrroline-5-carboxylic acid reductase 1 (PYCR 1), a proline biosynthetic enzyme co-expression was studied using immunofluorescence analysis.

RESULTS
HOXC10 is highly expressed in human and mouse GBM tissues. HOXC10 was upregulated only in the high-grade/aggressive cell line [EGFRvIII; p16-/- & GFAP Cre] and demonstrated increased expression with p16 deletion in the mouse glioma cell line. Compellingly, TCGA analysis of GBM correlated the negatively prognostic p16 homozygous deletion (HD) with HOXC10 upregulation. Gene Ontology supports the role of HOXC10 for proline biosynthesis and metabolism. Immunofluorescence on mouse GBM sections revealed co-expression of HOXC10 and PYCR1. HOXC10 silencing significantly decreased GBM cell line proliferation, induced apoptosis, and decreased PYCR1 expression in vitro.

CONCLUSIONS
HOXC10 expression is increased in GBM and with p16 HD. HOXC10 silencing significantly decreased GBM cell line proliferation and decreased PYCR1 expression. HOXC10-mediated proline biosynthesis may present a novel target to improve GBM survival.
TMET-33. INVESTIGATING THE ROLE OF CHEMERIN SIGNALING IN GLIOBLASTOMA
Authors: Dessa Brianna , Wang Dazhi , Welford Scott 
Published: November 2024

Abstract
Glioblastoma multiforme (GBM) is one of the most common and lethal primary brain tumors in adults. Despite clinical efforts, patient prognosis remains poor with a median survival of approximately 14 months. Thus, identification of novel treatment avenues is needed. Metabolic rewiring is a hallmark of cancer and lipid homeostasis has an increasingly appreciated role in cancer cell survival. It has been shown that the disruption of lipid metabolic balance can lead to lipotoxicity, creating a new avenue in GBM treatment. Therefore, identifying methods to disrupt said lipid metabolic balance in GBM could provide a needed foothold. Previous studies from the lab have identified chemerin, a multifunctional adipokine encoded by the retinoic acid receptor responder 2 (RARRES2) gene, as an important and targetable lipid metabolism modulator in Clear cell renal cell carcinoma (ccRCC). Chemerin has also been implicated in the mesenchymal-phenotype promoting network between GBM cells and tumor-associated macrophages. Given similarities in GBM and ccRCC lipid metabolism and the existing role of chemerin in the tumor immune microenvironment in GBM, we hypothesize that chemerin drives GBM development by regulating lipid metabolism in addition to immune cell trafficking. This study aims to investigate the role and therapeutic opportunities of altered lipid metabolism in GBM by examining chemerin and its receptors (CMKLR1 and GPR1). Immunocompetent GBM mouse models generated through CRISPR-in utero electroporation (IUE) show that mice bearing RARRES2, CMKLR1, and GPR1 knockout tumors have prolonged survival. In addition, in vitro molecular inhibition of CMKLR1 in both human and murine GBM cell lines results in cell death. Ongoing studies involving in vitro CRISPR knockouts of RARRES2, CMKLR1, and GPR1 aim to elucidate the mechanisms by which in vivo inhibition of chemerin signaling results in slower tumor progression.
TMET-34. PYROPTOSIS IS AN ACQUIRED VULNERABILITY OF BRAIN METASTASES
Authors: Mobilio Daniel , Kieliszek Agata , Peterson Erik , Singh Kanwaldeep , Zhai Kui , Miletic Petar , Gwynne William , Ang Patrick , Venugopal Chitra , Chafe Shawn , Berg Tobias , Wahl Daniel , Singh Sheila 
Published: November 2024

Abstract
Metastasis, the spread of cancer cells from one part of the body to another, is a leading cause of death among cancer patients. Three particularly dangerous forms of metastases are the spread of lung, skin, and breast cancers to the brain. On average survival time of all brain metastasis (BM) patients is around 4 months, which is accompanied by a failing and undefined standard of care. We have strived to bridge the gap between novel safe therapeutics and brain metastasis patients by discovering and targeting metabolic vulnerabilities in brain metastases. Here, we conducted comparative metabolomic screening in patient-derived BM lines versus normal brain cells to identify dihydroorotate dehydrogenase (DHODH) as a cancer-selective targetable vulnerability. DHODH is an essential enzyme that is located within the inner membrane of the mitochondria which has a primary role in producing pyrimidine metabolites through the de novo uridine synthesis pathway and also contributes to the proper functioning of the electron transport chain. Through this, DHODH has been implicated in the essential functioning of energy metabolism, DNA and RNA synthesis, and most recently in the modulation of the immune system. In our studies we have elucidated the significant effect DHODH inhibitors and the induction of DHODH CRISPR knock-out has against the cell viability, sphere formation, and proliferation of patient derived BM samples in vitro and in vivo. Furthermore, through metabolomics we have discovered that following DHODH perturbation, there is a significant increase in a signaling lipid (D-ethryo-Dihydrosphingosine) that specifically inhibits Protein Kinase C (PKC) and initiates Gasdermin E (GSDME) mediated pyroptosis. By uncovering this mechanism we have discovered GSDME mediated pyroptosis is an aquired vulnerability of brain metastases. Overall, this study highlights the translational potential of DHODH inhibitors in BM and elucidates novel mechanistic underpinnings of nucleotide deprivation within the context of cell death.
TMET-37. TARGETING LIPID MEDIATED NON-CANONICAL CELL DEATH IN MALIGNANT GLIOMA
Authors: Salinas Jennifer , Cadet Dimitri , Smolev Sarina , Iyer Dhruva , Loo Caitlyn , Lee Weaverly , Dixon Scott , Nathanson David 
Published: November 2024

Abstract
Resistance to canonical cell death mechanisms (e.g. apoptosis) is a hallmark of glioma and consequently driving the dismal outcomes of patients with glioma. Recent work has demonstrated gliomas are susceptible to non-apoptotic forms of cell death mediated by rewired lipid metabolism. Here we explored whether gliomas are vulnerable to other lipid-dependent forms of cell death. Our investigation revealed a large subset of patient-derived glioma cells that are exquisitely sensitive to a novel cell death pathway dependent on palmitate. Intriguingly, sensitivity to this type of cell death was linked to glioma tumor cells having a proneural identity and a specific enrichment in sphingolipid metabolic features. The catabolism of glioma sphingolipids established palmitate pools for protein S-palmitoylation, a necessary requirement to trigger palmitate mediated cell death in glioma, which was coupled to the exclusive expression of palmitoyl acyltransferases unique to proneural glioma tumors. Ongoing efforts aim to explore the mechanistic link between glioma identity, lipotype and susceptibility to palmitate dependent lethality. Taken together, these results identify a new approach to drive glioma cell death by targeting non-canonical cell death mediated by rewired glioma lipid metabolism.