bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIMG-20. METABOLIC BIOMARKERS IN MICRODIALYSATE OF IDH-1 MUTANT TUMORS
Authors: Rajani Karishma , Carlstrom Lucas , Jacobs Joshua , Schroeder Mark , Olson Ian , Hainy Matthew , Oh Juhee , Elmquist William , Sarkaria Jann , Burns Terry 
Published: March 2021

Abstract
Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system, with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors presents opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from patient-derived xenografts (PDX) harboring mutant IDH-1 (R132H). Perfusates were collected from intra-cranial tumors in athymic nude mice sampled at baseline and 72h post treatment with temozolomide (TMZ), an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment. Perfusates were analyzed via untargeted metabolomic profiling using liquid chromatography-mass spectrometry. Tumor specific metabolites such as (D)-2 hydroxyglutarate, were detected in microdialysate from IDH-1 mutant tumor bearing mice compared to non-tumor bearing mice. We also found high levels of metabolites such as 5-methylthioadenosine, and dimethylarginine and wide range of amino acids in microdialysate from IDH-1 mutant tumor bearing mice. TMZ treatment induced changes to metabolites in creatine and histidine metabolism. Our results indicate that microdialysis is a feasible technology to identify metabolomics-based biomarkers in IDH1-mutant gliomas and their response to therapy. We suggest that in vivo intratumoral microdialysis over several days could yield metabolic pharmacodynamic biomarkers of value to therapeutic translation for IDH-mutant gliomas.
BIMG-22. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS
Authors: Li Xianqi , Andronesi Ovidiu , Strasser Bernhard , Jafari-Khouzani Kourosh , Cahill Daniel , Dietrich Jorg , Batchelor Tracy , Bendszus Martin , Neuberger Ulf , Vollmuth Philipp 
Published: March 2021

Abstract
Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
BIMG-23. SINGLE-VOXEL VERSUS MULTI-SLICE MRSI IN PATIENTS WITH GLIOMA ON A KETOGENIC DIET INTERVENTION
Authors: Munjapara Vasu , Kamson David , Berrington Adam , Strowd Roy , Schreck Karisa , Barker Peter 
Published: March 2021

Abstract

BACKGROUND
Ketogenic diet therapies (KDTs) may be beneficial by exploiting glioma metabolic vulnerabilities. The GLioma modified Atkins-based Diet study (GLAD; NCT02286167) evaluated systemic and cerebral (MR spectroscopy) biomarkers to determine the feasibility and biological effects of a KDT in glioma patients. While we observed metabolic changes in tumor and normal brain after KDT using single-voxel MRS (SV-MRS), optimal voxel placement was not always achieved. AIMS: We performed an exploratory analysis comparing cerebral metabolite changes using multi-slice MRSI (MS-MRSI) versus SV-MRS acquisition.

METHODS
We evaluated four patients from the GLAD study (mean age 39years; 2 female, 3 AA IDH-mutant, 1 GBM IDH-wildtype) who underwent MRS at baseline and following eight weeks of KDT. SV-MRS (sLASER, TR/TE 2.2s/34ms) was acquired from a 2x2x2cm voxel placed in the residual tumor and the contralateral homologous brain. MS-MRSI was acquired with a multi-slice spin echo sequence (TR/TE 3.6/144ms, 4 slices, nominal resolution 13x7x7mm, SENSE factor 3) and maps of total choline (tCho), total N-acetyl-aspartate (tNAA), and lactate (Lac) were reconstructed and normalized relative to creatine. Metabolite levels were measured on the MS-MRSI maps using a region of interest placed in the same areas studied with the SV-MRS.

RESULTS
Lesional tCho and tNAA levels showed strong correlation between SV-MRS and MS-MRSI both at baseline (Pearson’s r=0.92 and 0.97, respectively) and after 8 weeks of KDT (r=0.96 and 0.84, respectively). tCho and tNAA correlated less robustly between SV-MRS and MS-MRSI in the contralesional region (r=0.56–0.96). Lesional Lac was significantly lower after KDT (1.01±0.48 versus 0.59±0.24, paired t-test p=0.02).

CONCLUSIONS
While SV and MS-MRSI provided generally concordant lesional results, MS-MRSI offers added potential to map regional variations not captured by SV-MRS and thus may better define the control regions. MS-MRSI detected a decrease in tumoral lactate levels following study intervention, suggesting KDT-related changes in tumoral energy metabolism.
DDRE-06. REGULATION OF TUMOR MICROENVIRONMENT VIA ENDOTHELIAL-TO-MESENCHYMAL TRANSITION BLOCKADE IN GLIOBLASTOMA-ASSOCIATED BRAIN ENDOTHELIAL CELLS
Authors: Marin’ Ramos Nagore I , Jhaveri Niyati , Thein Thu Zan , Chen Thomas C 
Published: March 2021

Abstract
Glioblastoma multiforme (GBM) is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature. Glioma stem cells (GSC) are a subpopulation of cells resistant to treatments and considered responsible for tumor recurrence. GSC are found in the vascular niches of the tumors, where endothelial cells (EC) secrete factors that stimulate GSC self-renewal. There are several studies regarding the effects of the vasculature on CSC and tumorigenesis, but little is known about how GSC affects the vasculature. Resistance to therapies and tumor recurrence greatly rely on the pro-angiogenic nature and aberrant vasculature of GBM. The endothelial-to-mesenchymal transition (EndMT) supports the pro-angiogenic and invasive characteristics of GBM. Hence, blocking the EndMT would be a promising approach to inhibit tumor progression and recurrence. We have examined the dynamic cross-talk between GSC and EC during EndMT. We demonstrate that GSC induce EndMT in brain endothelial cells (BEC), through a collaboration between TGF-β and Notch pathways, nicotinamide N-methyltransferase upregulation and other key signaling routes. Elucidating the cells and molecular pathways responsible for this process represents a milestone in the understanding of the tumor microenvironment and will help develop novel treatments in glioma therapy. One promising treatment, developed by our research group, is the conjugate of temozolomide and perillyl alcohol (POH), NEO212. This drug blocks EndMT induction in BEC and reverts the mesenchymal phenotype of tumor-associated BEC (TuBEC), reducing the invasiveness and pro-angiogenic properties of GBM in vitro and in vivo. We are currently performing Investigational New Drug (IND)-enabling studies, and we foresee that NEO212 will be of great clinical value for the treatment of GBM.
DDRE-11. TARGETING FATTY ACID BIOSYNTHESIS IN GLIOBLASTOMA
Authors: Eyme Katharina M , Neustadt Rudolph , Badr Christian E 
Published: March 2021

Abstract
We recently provided evidence that endoplasmic reticulum (ER) stress promotes fatty acid (FA) biosynthesis in glioblastoma (GBM) cancer stem cells (GSCs). We determined that Stearoyl CoA Desaturase 1 (SCD), a key FA desaturase, is essential for regulating ER homeostasis in GSCs, and showed that these cells are highly susceptible to pharmacological perturbation of SCD activity. An impaired SCD activity leads to the toxic accumulation of saturated FA and activates cell death signaling mediated by the ER sensor Inositol-requiring enzyme 1 (IRE1). This in turn promotes an IRE1-mediated mRNA decay of key DNA damage repair genes and impairs the ability of GSCs to repair DNA damage caused by radiation or chemotherapy. Consequently, combining SCD inhibition with temozolomide (TMZ) leads to major cytotoxicity both in TMZ-sensitive, and TMZ-resistant patient-derived GBM cells. Pharmacological inhibition of SCD delivered through the nasal route in mice, had a remarkable therapeutic benefit in patient-derived orthotopic GSCs mouse models, yet the modest brain permeability of the currently available SCD inhibitors precludes their clinical translation. To overcome this challenge, we have recently acquired a first-in-class, clinically relevant SCD inhibitor. This compound has undergone extensive pharmacokinetic and pharmacodynamic studies which confirmed brain permeability, efficacy, and safety in small animals and non-human primates. We show that the combination of this SCD inhibitor with TMZ is effective both in cultured GSCs, and in preclinical GSCs orthotopic mouse models. Our results support the clinical investigation of this new class of SCD inhibitors, in combination with TMZ, in patients diagnosed with GBM.
DDRE-16. CYSTEINE IS AN ESSENTIAL AMINO ACID IN GLIOMAS
Authors: Ruiz-Rodado Victor , Dowdy Tyrone , Yung Jinkyu , Dios-Esponera Ana , Lita Adrian , Kramp Tamalee , Camphausen Kevin , Gilbert Mark , Larion Mioara 
Published: March 2021

Abstract

BACKGROUND
Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo.

METHODS
Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments involving different probes such as 13C-methyl-Methionine, 13C-C3-Cysteine, 13C-C3,3’-Cystine, 13C-C3-Serine and 13C-U-Glutamine and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS.

RESULTS
We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. We also found that methionine cycle is disconnected from the transsulfuration pathway based on 13C-tracing data and protein expression levels of cystathionine synthase and cystathioninase. Accordingly, cysteine-related metabolites such as GSH, involved in REDOX hemostasis, are downregulated, revealing a hypersensitive phenotype to ROS. Animal models upon a cysteine/cystine-free diet experienced an increase in survival and elevated levels of oxidative stress in tumor tissue.

CONCLUSION
This results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions.
DDRE-19. PHASE 0/I TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH RADIATION TO OVERCOME GLIOBLASTOMA TREATMENT RESISTANCE BY TARGETING DE-NOVO PURINE METABOLISM
Authors: Umemura Yoshie , Sun Yilun , Junck Larry , Leung Denise , Kim Michelle , Al-Holou Wajd , Sagher Oren , Heth Jason , Lyssiotis Costas , Marini Bernard , Lawrence Theodore , Wahl Daniel 
Published: March 2021

Abstract

BACKGROUND
Radiation resistance is one of the major limitations for effective control of glioblastoma. Guanosine triphosphate (GTP) supplementation promotes glioblastoma radioresistance. Conversely, GTP depletion overcomes glioblastoma radioresistance by slowing the repair of radiation-induced DNA damage. Mycophenolate mofetil (MMF) inhibits de novo GTP synthesis by inhibiting the key enzyme, inosine-5′-monophosphate dehydrogenase, and radiosensitizes glioblastoma in mice. These pre-clinical findings have led to Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined with Radiation Therapy in Recurrent Glioblastoma (NCT04477200) to measure the concentration of active metabolite of MMF in glioblastoma, and to determine the safe dose of MMF when given in combination with radiation.

METHODS
Key eligibility criteria are age ≥18, patients with Karnofsky Performance Scale score ≥60, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection or biopsy (phase 0). Those with tumor involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. Eight participants will receive MMF 500–2000 mg PO BID for one week before surgery (phase 0). Approximately 30 subjects will receive MMF 250–2000 mg PO BID (starting: 1000mg) on TITE-CRM dose escalation model (phase I).

RESULTS
From 7/2020 to 11/2020, two phase 0 and three phase I subjects have completed MMF treatment without notable toxicity. Additionally, correlative measurements of the activity of de novo GTP synthesis are explored. The anticipated study duration is 48 months.

CONCLUSION
The results of this trial will aid in designing a randomized clinical trial to determine the efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness. MMF is widely available and inexpensive, so if positive efficacy result is observed, a brisk acceptance of MMF combined with the standard of care is anticipated.
DDRE-20. TARGETING SPHINGOLIPID PATHWAY REVEALS VULNERABILITY IN IDH1MUT GLIOMA
Authors: Dowdy Tyrone , Zhang Lumin , Celiku Orieta , Movva Sriya , Ruiz-Rodado Victor , Lita Adrian , Larion Mioara 
Published: March 2021

Abstract

BACKGROUND
While central carbon metabolism has been studied extensively in cancer, lipidomic research is sparse. Sphingolipids participate in cellular functions including secondary messengers, lymphocyte trafficking, inflammation, angiogenesis, migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role to tumor phenotype. Our investigation into metabolic alterations involving sphingolipid pathway in patient-derived IDH1mut glioma cultures aimed to identify points of metabolic vulnerability.

METHODS
Dysregulation of sphingolipid metabolism was interrogated for brain tumor cultures via LCMS. Expression of enzymes within the pathway was assessed for IDHmut 1/2 and IDHWT glioblastoma patient cohorts via The Cancer Genome Atlas (TCGA) analysis and Western blot for tumor cultures. Biostatic drug response was examined via viability and cytotoxicity assays.

RESULTS
We probed the effect that decreasing D-2HG levels with IDH1mut inhibitor (AGI5198) treatments had on sphingolipid metabolism in tumor cultures. The probe revealed N,N-dimethylsphingosine (NDMS), and sphingosine were significantly elevated, while sphingosine-1-phosphate (S1P) was downregulated in IDH1mut cultures following treatment. Drug panel screening revealed that SPHK inhibitor (SPHKi), N,N-dimethylsphingosine in combination with sphingosine triggered lethal dose-dependent response in IDH1mut cultures; contrary to IDHWT. Westerns presented differential expression of SPHK1 and SPHK2 in IDHWT glioblastoma cells, while IDHmut exclusively expressed SPHK1.

CONCLUSION
This novel discovery showed how targeting sphingolipid metabolism in IDH1mut gliomas presents therapeutic implications. Elevated S1P was reported particularly for malignant glioblastomas in prior studies; whereas our research revealed relatively low S1P in the IDHmut compared with IDHWT cultures. In addition to reduced or silenced expression of SPHK2, we postulate that S1P levels in IDHmut gliomas might be closer to a critical threshold allowing treatment with SPHK1i to effectively suspend proliferation and anti-apoptotic defense mechanisms. Our findings revealed that the manipulation of pivotal, endogenous sphingolipids can ultimately trigger apoptosis in IDHmut gliomas. Future studies will probe these targets in preclinical models.
DDRE-29. DE NOVO PYRIMIDINE SYNTHESIS IS A TARGETABLE VULNERABILITY IN IDH-MUTANT GLIOMA
Authors: Shi Diana D , Wang Adam C , Levitt Michael M , Endress Jennifer E , Xu Min , Gao Wenhua , Khanal Januka , Bonal Dennis , Kornblum Harley I , Nguyen Quang-De , Gradl Stefan , Sutter Andreas , Jeffers Michael , Janzer Andreas , Cahill Daniel P , Ligon Keith L , Abdullah Kalil G , Harris Isaac S , Kaelin William G , McBrayer Samuel K 
Published: March 2021

Abstract
70–90% of lower-grade gliomas and secondary glioblastomas harbor gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1), causing overproduction of the oncometabolite (R)-2-hydroxyglutarate [(R)-2HG]. Although inhibitors of mutant IDH enzymes are effective in other cancers, including leukemia, they have shown guarded efficacy in preclinical and clinical brain tumor studies, thus underscoring the need to identify additional therapeutic targets in IDH mutant glioma. We sought to identify tumor-specific metabolic vulnerabilities induced by IDH1 mutations that could be exploited therapeutically. To uncover such vulnerabilities, we conducted a chemical synthetic lethality screen using isogenic IDH1 mutant and IDH1 wild-type (WT) glioma cell lines and a novel metabolic inhibitor screening platform. We discovered that IDH1 mutant cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). This vulnerability is specific because inhibitors of purine nucleotide metabolism did not score in our screen. We validated that the cytotoxicity of pyrimidine synthesis inhibitors is on-target and showed that IDH1 mutant patient-derived glioma stem-like cell lines are also hyperdependent on de novo pyrimidine nucleotide synthesis compared to IDH1 WT lines. To test pyrimidine synthesis dependence of IDH1 mutant gliomas in vivo, we used a brain-penetrent DHODH inhibitor currently undergoing evaluation in leukemia patients, BAY 2402234. We found that BAY 2402234 displays monotherapy activity against gliomas in an orthotopic xenograft model of IDH1 mutant glioma, with an effect size that compared favorably with radiotherapy. We also developed novel genetically engineered and allograft mouse models of mutant IDH1-driven anaplastic astrocytoma and showed that BAY 2402234 blocked growth of orthotopic astrocytoma allografts. Our findings bolster rationale to target DHODH in glioma, highlight BAY 2402234 as a clinical-stage drug that can be used to inhibit DHODH in brain tumors, and establish IDH1 mutations as predictive biomarkers of DHODH inhibitor efficacy.
DDRE-30. THERAPEUTIC TARGETING OF DISRUPTED METABOLIC STATE IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Mbah Nneka , Myers Amy , Chung Chan , Thompson Joyce , Shan Mengrou , Hong Hanna , Koschmann Carl , Venneti Sriram , Lyssiotis Costas 
Published: March 2021

Abstract

BACKGROUND
Diffuse Intrinsic Pontine Glioma (DIPG) is a uniformly fatal pediatric brainstem tumor and the leading cause of brain-tumor related deaths in children. It is therefore imperative to identify novel treatment strategies for this aggressive and devastating disease. Metabolic reprogramming in tumors and in the tumor microenvironment contribute to evasion of therapy and tumor recurrence. The goal of this study was to identify and therapeutically target metabolic vulnerabilities in DIPG that mediate aggressiveness and treatment resistance.

METHODS
DIPG tumors are marked by cellular heterogeneity and are driven by a population of cells with stem cell properties. We took a comprehensive metabolomics and transcriptomic screening approach to determine the operative pathways in the tumor driving stem cell compartment. To demonstrate efficacy and potential therapeutic window of activity, we treated DIPG tumors with clinically available and brain-penetrant inhibitors of the identified dysregulated metabolic pathways.

RESULTS
Our multi-omics analyses revealed that tumorigenic patient-derived DIPG cells significantly upregulate metabolic programs including cholesterol biosynthesis and mitochondrial oxidative phosphorylation (OXPHOS) compared to DIPG cells that were induced to undergo differentiation (events associated with a loss of tumorigenic capabilities). The therapeutic targeting of DIPG tumors with clinically available and brain penetrant inhibitors of OXPHOS and cholesterol biosynthesis resulted in tumor cell killing and growth inhibition both in vitro and in vivo. Moreover, there was a therapeutic window of activity in tumorigenic DIPG cells compared with differentiated gliomas and non-malignant cells.

CONCLUSION
Our findings demonstrate that DIPG harbor perturbations in metabolic programs that can be exploited for therapeutic benefits. The results from this study defined the metabolic pathways operative in the tumor-driving population in DIPG and demonstrated efficacy of targeting these pathways.