bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES
Authors: Sammarco Alessandro , Eyme Katharina , Jha Roshani , Silva Willian Das Neves , Neustadt Rudolph , Ford Ian , Bensinger Steven J , Zappulli Valentina , Breakefield Xandra , Badr Christian E 
Published: November 2022

Abstract
Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids, is often upregulated in breast cancer brain metastasis (BCBM) and is considered a promising therapeutic target. However, the lack of brain penetrant SCD inhibitors limited their use in patients. This study aimed to investigate the therapeutic efficacy of a clinical-stage brain penetrant inhibitor of SCD to treat BCBM. We found that pharmacologic inhibition of SCD in multiple breast cancer cell lines induced significant cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed that the fatty acid desaturation index, which measures SCD activity, was significantly lower after treatment. SCD inhibition triggered endoplasmic reticulum (ER) stress and increased DNA damage due to a higher production of reactive oxygen species. Further, SCD inhibition decreased DNA damage repair by inhibiting homology-directed repair in vitro and in a mouse model of breast cancer. Notably, inhibition of SCD led to a significant decrease in tumor growth in a subcutaneous mouse model of breast cancer and a significant increase in overall survival in a BCBM mouse model. Cytotoxicity was enhanced when this SCD inhibitor was combined with either a DNA damage-inducing agent (temozolomide or radiation) or with a PARP inhibitor (Niraparib). Finally, we observed that combination therapy of SCD inhibition and Niraparib significantly increased overall survival in a BCBM mouse model. Our results suggest that inhibition of SCD alone or in combination with a PARP inhibitor is a promising therapeutic strategy to treat BCBM.
TMET-04. DETECTING DYNAMIC PYRUVATE TUMOR METABOLISM IN PATIENTS WITH GLIOMA USING HYPERPOLARIZED CARBON-13 METABOLIC IMAGING
Authors: Li Yan , Lupo Janine , Autry Adam , Vaziri Sana , Gordon Jeremy , Lafontaine Marisa , Hsin-Yu Chen , Kim Yaewon , Hu Jasmine , Ma Wendy , Villanueva-Meyer Javier , Larson Peder , Xu Duan , Bush Nancy Ann Oberheim , Clarke Jennifer , Vigneron Daniel , Chang Susan M 
Published: November 2022

Abstract

INTRODUCTION
Hyperpolarized carbon-13 (HP-13C) MR enables rapid dynamic imaging of metabolic pathways in the human brain using non-toxic, non-radioactive metabolites as tracers. This study presents our unique experience on the benefit of using [1-13C]pyruvate and [2-13C]pyruvate MR for evaluating patients with glioma.

METHODS
132 scans (71 using an integrated 13C /1H coil) including steady-state 1H-MRSI (~10 min) and dynamic HP-13C imaging (60 sec) following injection of HP [1-13C]pyruvate (N=125) or [2-13C]pyruvate (N=7) were acquired from 46 patients with glioma (18F/28M; 15 IDH-mutant, 27 IDH-wildtype, 4 IDH-status-unknown). Maps of temporally-summed 13C-metabolite signals, ratios, and kinetic rate constants were calculated for contrast-enhancing, nonenhancing, and normal-appearing-white-matter (NAWM) regions and compared to steady-state metabolic metrics.

RESULTS
The only adverse event, in a single patient, was a burning sensation after the injection that resolved after saline flush. The mean time-to-injection of HP probes was 58.6±14.0 sec. Signal-to-noise ratios of [1-13C]lactate and [13C]bicarbonate within the NAWM from the HP [1-13C]pyruvate data were 53±39 and 13±6, respectively. The SD/mean of repeated injections (N=3) for lactate/pyruvate and pyruvate-to-lactate conversion rates were 3.8±3.1% and 6.5±3.1% in the NAWM, respectively. Patients with progressive GBM had significantly higher lactate/pyruvate and lower bicarbonate/lactate (p&lt; 0.05) in contrast- and non-enhancing lesions compared to NAWM. Significantly elevated lactate/pyruvate and reduced bicarbonate/lactate (p&lt; 0.01) were found in contrast-enhancing compared to nonenhancing regions, whereas choline/NAA and steady-state 1H-lactate levels were similar. HP [2-13C]pyruvate data showed reduced glutamate/pyruvate and pyruvate-to-glutamate conversion rates in T2 lesions compared to contralateral normal-appearing brain in IDH-mutant gliomas, consistent with known metabolic reprogramming.

CONCLUSION
This study demonstrates the potential benefit of dynamic HP-13C MRI for evaluating patients with glioma, which provides unique and spatially distinct contrast compared to steady-state metabolic imaging. Ongoing studies will further characterize dynamic metabolism in specific glioma subtypes and provide biomarkers for evaluating responses to treatment.
TMET-20. TERT ACTS VIA FOXO1 TO ALTER REDOX METABOLISM IN BRAIN TUMORS
Authors: Batsios Georgios , Taglang Celine , Tran Meryssa , Gillepspie Anne Marie , Viswanath Pavithra 
Published: November 2022

Abstract
Telomere maintenance is a fundamental hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying imaging biomarkers of TERT can enable non-invasive assessment of tumor proliferation and response to therapy. Deuterium magnetic resonance spectroscopy (DMRS) following administration of 2H-labeled substrates recently emerged as a novel, clinically translatable method of monitoring metabolic activity in vivo. The goal of this study was to delineate metabolic reprogramming associated with TERT expression and to leverage this information for non-invasive imaging of tumor burden and treatment response in gliomas. Our results indicate that TERT expression is associated with elevated levels of the redox metabolite NADH in glioblastomas and oligodendrogliomas. Mechanistically, TERT expression is associated with inhibitory phosphorylation and cytosolic sequestration of FOXO1. FOXO1, in turn, negatively regulates nicotinamide phosphoribosyl transferase (NAMPT), which is the rate-limiting enzyme in NAD+ biosynthesis. As a result, TERT upregulates NAMPT, resulting in elevated steady-state pools of NAD+ and NADH. Concomitantly, FOXO1 negatively regulates the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. As a result, TERT upregulates the NADH/NAD+ ratio. Since elevated NADH and NADH/NAD+ ratio drive pyruvate conversion to lactate, we then examined whether DMRS-based imaging of [U-2H]-pyruvate metabolism reports on TERT expression in gliomas. Our results indicate that doxycycline-inducible TERT silencing significantly reduces lactate production from [U-2H]-pyruvate in tumor-bearing mice. Importantly, [U-2H]-pyruvate metabolism to lactate differentiates tumor from normal brain in vivo, including at clinical field strength (3T). Furthermore, [U-2H]-pyruvate reports on early response to treatment with TERT inhibitors or with radiochemotherapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by magnetic resonance imaging. Collectively, our studies integrate a mechanistic understanding of TERT biology with innovative imaging that has the potential to improve assessment of tumor burden and treatment response for glioma patients.
TMET-26. PRIMARY OLIGODENDROGLIOMA CELL CULTURE VIABILITY: AN IN VITRO STUDY WITH METABOLIC MODULATORS
Authors: Villaverde Marcela , Arias Elsa Hincapié , Merenzon Martin , Mazzon Alejandro , Seoane Eduardo , Belgorosky Denise , Eiján Ana Maria 
Published: November 2022

Abstract
Oligodendrogliomas are tumors that develop from oligodendrocytes, the myelinating cells of the central nervous system. Oligodendrocytes are highly metabolically active cells that synthesize and transfer metabolites to neighboring cells. Given its intimate metabolic relation with neurons, we aim to investigate oligodendrocyte metabolism as an antitumoral target. A recurred oligodendroglioma WHO grade III was surgically removed from a 50-year patient after 10 years of progression-free disease. The tumor sample was mechanically digested and cultured at 37oC, 5% CO2, in DMEM: F12, 10 % FBS and antibiotics. Primary oligodendroglioma cells were trypsinized and seeded in a 96-well plate. After 24 hs, cells were treated with metabolic modulators: metformin (MET, mitochondrial complex II inhibitor, 5 mM), 2 deoxyglucose (2DG, hexokinase inhibitor, 1 mM), 6-aminonicotinamide (6AN, pentose phosphate pathway inhibitor, 50 µM) and/or 1400W and S-methylisothiourea (both iNOS inhibitors, 5 µM, and 50 µM respectively). Standard treatment with temozolomide (TMZ, 200 µM) was also performed. After 5 days of treatment, cells were stained with violet crystal. Two weeks after tumor sample digestion, a primary oligodendroglioma culture was successfully established. In vitro, proliferating cells appeared mostly undifferentiated with reduced branching complexity. Hexokinase inhibition by 2DG notoriously affected the viability of oligodendroglioma cells. Similar results were obtained with standard TMZ treatment. On the other hand, the inhibition of the pentose phosphate pathway by 6AN did not affect the cell monolayer. However, 6AN was able to increase the effect of MET as monotherapy. Both, MET and 2DG altered oligodendrocyte morphology inducing a more fusiform shape. Finally, iNOS inhibition modestly disrupted cell's monolayers and this effect did not seem to be improved by combinatory therapies. Glycolytic inhibitor 2DG resulted effective against oligodendroglioma cells. Whereas further studies are needed to validate these results, a better understanding of metabolic susceptibility could allow the development of better-targeted and more-effective therapeutic approaches.
TMET-27. DEXAMETHASONE-ASSOCIATED GENE EXPRESSION AND METABOLITE MODIFICATIONS IN GLIOMA TISSUE AND CELL CULTURES
Authors: Trautwein Christoph , Zizmare Laimdota , Maise Louise , Becker Hannes , Skardelly Marco , Tatagiba Marcos , Merk Daniel , Pichler Bernd J , Tabatabai Ghazaleh 
Published: November 2022

Abstract
Altered metabolism is amongst the hallmarks of cancer including diffuse glioma. We have recently presented a large database with tissue metabolites that are modulated by IDH1 mutation in diffuse glioma. Furthermore, we suggested potential candidate biomarkers for prospective validation that could serve for further refinement of prognostic groups in IDH1-mutated glioma. Glucocorticoids, particularly dexamethasone, are widely used in neuro-oncology and trigger a variety of metabolic effects, e.g. systemic adverse events including steroid-induced diabetes and truncal weight gain. In this subsequent study, we investigated dexamethasone-associated modifications of metabolite profiles in human glioma tissue (n=24 treated with dexamethasone, n=77 without) and in glioma cell lines. We performed ex-vivo Nuclear Magnetic Resonance (NMR) spectroscopy and RNA sequencing to discover comparison-specific metabolites and pathways. Dexamethasone-associated pathways involved increased energy and growth metabolism. Furthermore, we characterized dexamethasone-induced metabolite modulations in glioma cell lines to investigate dexamethasone effects in a rather homogeneous glioma cell population. We investigated the cellular effects of selected significant metabolites in acute cytotoxicity and clonogenic survival assays. Our data provide further insight into dexamethasone-associated metabolic effects in cell lines and tissue that might be relevant for further studies and its use in clinical practice.
TMET-29. THE GLUTAMINE TRANSPORTER SLC1A5 IS ASSOCIATED WITH REWIRING OF AMINO ACID, LIPID, AND IMMUNE PATHWAYS AND TUMOR PROGNOSIS IN PEDIATRIC BRAIN CANCERS
Authors: Kraya Adam A , Jin Run , Zhao Chao , Familiar Ariana , Storm Philip B , Wellen Kathryn , Resnick Adam C , Nabavizadeh Ali 
Published: November 2022

Abstract
Glutamine transporters play an important role in supporting increased tumor nutritional demands, often through overexpression of the solute carrier (SLC) family of membrane transporters. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes, lipid metabolism and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes, we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 0.032 and p = 9.8e-4) and shorter PFS in LGG (p = 0.022). We found a universally higher expression of ATP citrate lyase (ACLY) and Acetyl-CoA carboxylase 1 (ACC) relative to normal brain tissue across all histologies. BRAF driven low grade gliomas and SHH-driven medulloblastomas showed differential expression of ACLY compared to other histologies. In addition, Acyl-CoA synthetase short chain family member 1 and 2 (ACSS1 and 2) were universally downregulated in pediatric gliomas, indicating that pediatric CNS tumors seem to rely on ACLY over ACSS for lipid synthesis. Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. SLC1A5 correlated negatively with pathways associated with lipid metabolic breakdown/degradation and correlated positively with pathways associated with lipid biosynthesis. In conclusion, our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain tumors and can be exploited with theranostic approaches and amino-acid PET imaging.
TMET-30. ENHANCED RADIOSENSITIZATION OF GLIOMAS BY METABOLIC TARGETING OF SALVAGE PATHWAY OF NAD SYNTHESIS THROUGH NAMPT INHIBITION
Authors: Sharma Pratibha , Xu Jihong , Huo Longfei , Ju Zhenlin , Li Ziyi , Ban Kechen , Landesman Yosef , Sampath Deepa , Puduvalli Vinay 
Published: November 2022

Abstract

BACKGROUND
Pathway-specific targeted agents have failed to improve outcome in patients with high grade gliomas. Tumor recurrence is driven by glioma heterogeneity and emergence of therapy-resistant subpopulations. We have previously reported that metabolic targeting of NAMPT, the rate limiting enzyme in the NAD salvage synthesis pathway, circumvents glioma heterogeneity and induces cytotoxicity by mitochondrial membrane depolarization and generation of reactive oxygen species. Based on these data, we examined the potential for NAMPT inhibition to synergize with ionizing radiation to enhance glioma cytotoxicity in vitro and in vivo.

METHODS
Using a panel of genetically heterogeneous patient-derived glioma stem-like cells (GSC), we examined the effects of NAD targeting using KPT9274, a potent NAMPT inhibitor, in combination with ionizing radiation on cell proliferation and clonogenicity using Cell Titre Glo assay, colony formation assays and secondary sphere formation. Changes in DNA damage-related proteins were visualized by immunofluorescence assay and confocal microscopy. Effects on gene expression and protein levels were assessed using western blot, reverse phase protein array (RPPA) and RNA Seq.

RESULTS
NAMPT inhibition reduced cell proliferation rate, self-renewal and clonogenic capacity in vitro. Combining KPT-9274 with ionizing radiation caused synergistic inhibition of secondary sphere and colony formation of GSC. RPPA and RNASeq results showed downregulation of several DNA repair proteins which was further confirmed using immunofluorescence staining indicating a crucial role for these proteins in glioma resistance to therapies. Results of ongoing in vivo studies to assess the PK/PD, drug toxicity and survival benefits of this combination therapy in orthotopic GSC intracranial glioma mouse model will be reported.

CONCLUSIONS
Our results suggest that metabolic targeting through NAMPT inhibition sensitizes glioma cells to radiotherapy. Ongoing studies delineating the mechanistic basis of these effects and their impact in vivo as a potential rationale for clinical assessment will be reported.
TMET-38. LOSS OF FUNCTION OF CDK7 IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA
Authors: Nguyen Trang , Shang Enyuan , Shu Chang , Akman Hasan , Izar Benjamin , Westhoff Mike-Andrew , Karpel-Massler Georg , Bruce Jeffrey , Canoll Peter , Siegelin Markus 
Published: November 2022

Abstract
CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7i elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7i inhibitors with blockers of FAO (etomoxir) or cellular respiration (gamitrinib) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Moreover, the combination treatment activated intrinsic apoptosis through a reduction of both Mcl-1 and Bcl-xL as demonstrated by rescue experiments. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.
TMIC-04. TARGETING AN ECM PROTEIN INVOLVED IN BREAST CANCER BRAIN METASTASES WITH AN ONCOLYTIC HSV-1
Authors: Rivera-Caraballo Kimberly , Yoo Ji young , Hong Bangxing , Kaur Balveen 
Published: November 2022

Abstract
The beta-1 subunit of integrins (CD29) is important for cell-extracellular matrix interactions. CD29 expression is increased in breast cancer cells, and it promotes their invasion, migration, and intravasation, all of which can result in breast cancer brain metastasis (BCBM). While CD29 expression can be correlated to poor prognosis of breast cancer patients, the median survival of BCBM patients predicted to have better prognosis is 36 months. Despite current BCBM treatments such as craniotomy, reaching the metastatic site is often challenging. Modified viral vectors, such as oncolytic herpes simplex virus (oHSV), have been clinically approved for the treatment of malignant melanoma and brain tumors, as they infect and selectively kill tumor cells. Previously, we identified that combination of oHSV and humanized CD29 blocking antibody (OS2966, aCD29) enhanced viral replication by reducing antiviral immune response, increased tumor cell killing, and rendered survival benefit to tumor bearing mice with intra-tumoral, but not systemic, oHSV administration. These findings suggested that the antitumor efficacy of the therapeutic combination required intratumoral delivery of anti-CD29, since the antibody could not penetrate the blood brain barrier and reach intracranial tumors. To overcome this, we report the generation of an oHSV encoding the scFv-Fc fragment of this antibody (HSV-aCD29), which retains its oncolytic function, and evaluate the impact of HSV-aCD29 on the CD29 downstream signaling. We will further characterize the safety, antitumor efficacy, and assess the immune response to HSV-aCD29 in vitro and in vivo. We anticipate that compared to our control virus, HSV-aCD29 will block CD29 activity which will reduce antiviral immune responses and enhance tumor cell lysis, thus improving oHSV efficacy. Together, this study proposes the blockade of CD29 with the targeted delivery of a CD29 blocking antibody mediated by a novel oHSV as a potential synergistic therapy against BCBM.
TMIC-05. SINGLE-CELL MULTI-OMIC ANALYSIS OF SPORADIC VESTIBULAR SCHWANNOMAS REVEALS SCHWANN CELLS WITH AN INJURY PHENOTYPE AND AN ASSOCIATION BETWEEN TUMOR SIZE AND MACROPHAGE INFILTRATE
Authors: Patel Bhuvic , Barrett Thomas , Pugazenthi Sangami , Khan Saad , Yim Aldrin , Buchman Craig , Patel Akash , Petti Allegra , Puram Sid , Kim Albert 
Published: November 2022

Abstract
Vestibular schwannomas (VS) comprise 8% of primary brain tumors, with rising prevalence due to increased detection by imaging. How intertumoral heterogeneity and differences within the tumor microenvironment (TME) contribute to the pathogenesis of VS remains poorly understood. We performed single-cell RNA sequencing (scRNA-seq) on 15 sporadic VS with paired single-nucleus assay of transposase accessible chromatin sequencing (snATAC-seq) on 7 tumors. Dimension reduction analysis revealed diverse Schwann, immune—predominantly macrophage, and stromal cell populations. Schwann cells adopted multiple unique functional states, such as repair-like, myelinating, and hypoxia-response, reflecting undescribed intratumoral heterogeneity within VS-associated Schwann cells. Remarkably, VS-associated Schwann cells were found to be phenotypically similar to Schwann cells in the setting of peripheral nerve injury, which is robustly associated with macrophage recruitment. Indeed, using our scRNA-seq atlas to perform deconvolution analysis of a broader cohort of VS, including newly sequenced (n = 22) and published bulk RNA-sequencing datasets (n = 153), we found variation in proportion of immune cells was strongly correlated with the proportion of macrophage infiltrate (R,2 = 0.86, p &lt; 0.001). Furthermore, we found that macrophage/monocyte lineage cells represent a disproportionately large number of cycling cells in the VS TME, a finding corroborated by immunohistochemistry. Clinically, tumors with high macrophage infiltrate were associated with larger tumor size (Fisher’s exact test p = 0.007). Together, these findings suggest macrophages play an important role in VS pathogenesis. We therefore sought to characterize potential cell-to-cell interactions between Schwann cells and macrophages in our scRNA-seq atlas. Ligand-receptor analysis revealed several cytokines expressed by Schwann cells with cognate receptors expressed by macrophages, including MIF, SPP1, MDK, SEMA3C and IL34, which may be responsible for recruiting macrophages. In summary, we describe previously uncharacterized cellular diversity within VS, highlight an association between macrophage infiltration and clinical phenotypes, and identify potential therapeutic targets for VS treatment.