bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCIDOT-40. THERAPEUTIC GENOME EDITING AS A NOVEL TREATMENT FOR GBM
Authors: Rosenblum Daniel , Gutkin Anna , Peer Dan 
Published: November 2019

Abstract
Glioblastoma multiforme (GBM), is the most aggressive form of glioma, a brain tumor that arises from glial cells. GBM is considered a complex malignancy with multiple gene mutations, aberrations, and overexpression together with high infiltration rate and resistance to apoptosis. The current treatment consists of surgical resection, aggressive radiation and chemotherapy regimen. This therapeutic strategy had not changed since 2005 when the chemotherapy Temozolomide was approved. This therapeutic approach extended GBM patients’ life expectancy to approximately 15 months since diagnosis. Although recent progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, the majority of these leading drug candidates remain ineffective. Therefore, novel and effective treatment to GBM presents an unmet need. Lipid nanoparticles (LNPs) are the most clinically advanced delivery platform to date for systemic administration of RNA therapeutics, with the recent approval of Patisiran, siRNA encapsulating LNPs. In recent years, several gene editing technologies have been discovered in bacteria, enabling precise and permanent manipulations at the DNA level. The most advanced and versatile system is based on the CRISPR nuclease Cas9. The recognition of its target chromosomal DNA by Cas9 results in a site-specific double-strand break (DSB), that eventually results in gene disruption. This approach opens multiple venues for research and treatment of diseases including cancer. We have utilized CRISPR encapsulating LNPs to promote a therapeutic gene editing by disrupting key GBM survival genes in vitro in murine and human GBM cell lines as well as in vivo in an aggressive syngeneic GBM mouse model. Our results suggest that treatment with our LNPs based system can specifically and efficiently target GBM cells in vitro and in vivo. Our CRISPR-LNPs based platform could potentially mature to a clinical trial, and ultimately might become a new therapeutic modality in GBM.
SCIDOT-45. MAGNETIC FIELD STRUCTURE OF THE HÆLO™ PEDIATRIC SYSTEM
Authors: Peterson Eric , Figueroa Xavier , Butters Mike , Woodcock Amanda , Brown Dan , Ferguson Ken 
Published: November 2019

Abstract

BACKGROUND
The Hælo pediatric system, an investigational medical device intended to treat diffuse midline glioma (DMG), emits a magnetic field intended to disrupt the growth of DMG tumors. The Hælo headcoil is positioned on the back of the patient’s head; the field envelopes the patient’s head and the specific frequencies of the field penetrate the skull and brain tissue without any significant attenuation.

METHODS
The shape and intensity of the magnetic field emitted by the Hælo headcoil were measured using a triaxial magnetic sensor, which measures the flux density along three orthogonal axes. The headcoil is designed to conform to the back of the head and is not planar. To account for the slight difference in field shape due to the coil’s convex shape, the field was measured with the coil held in both a convex and concave position relative to the central plane. A custom-designed measurement system was used to position the sensor in a three-dimensional grid with 1 cm resolution (approximately 10,000 individual measurements for each coil position.) A test field with the same flux density produced by the Hælo pediatric system treatment field was used. The root mean square of the field along each axis was calculated and combined to yield the total flux density at each position. The datasets from each coil position were combined to create a complete three-dimensional map of the field generated by the headcoil.

RESULTS
The greatest flux density is proximal to the coil. The test field ranged from approximately 200 mGauss near the headcoil to 100 mG within the ellipsoid formed by the headcoil.

CONCLUSION
The field of the Hælo pediatric system encompasses the brain and portions of the brainstem, and thus delivers a targeted magnetic therapeutic to the common tumor locations for DMG.
SCIDOT-50. A RAT MODEL FOR LASER INTERSTITIAL THERMAL THERAPY FOR GLIOBLASTOMA: EFFECTS ON PERI-ABLATION BLOOD-BRAIN BARRIER AND IMPLICATIONS FOR POST-ABLATION CHEMOTHERAPY
Authors: Nagaraja Tavarekere , Ewing James , Farmer Katelynn , Valadie Grahm , Brown Stephen , Knight Robert , Cabral Glauber , Panda Swayamprava , Lee Ian 
Published: November 2019

Abstract
Laser interstitial thermal therapy (LITT) is a minimally invasive tumor cytoreductive treatment for recurrent gliomas, brain tumors in eloquent regions or otherwise inaccessible to traditional open surgery. LITT offers quicker recovery and shorter hospital stays as additional advantages. A laser fiberoptic catheter is positioned in the body of the tumor under magnetic resonance imaging (MRI) guidance via a twist drill hole in the skull. Using MR thermometry, the tumor is ablated by laser heating to lethal temperatures. The peri-ablation zones get heated to sub-lethal temperatures and subsequently recover. It has been reported in humans that opening of the blood-brain barrier (BBB) occurs, lasting several weeks after ablation. We have adapted Visualase®, a clinically available LITT system, for use in a rat glioblastoma model. Athymic female rats (n=7) were implanted with U251 tumor cells in one brain hemisphere. Tumor growth was monitored using MRI. When tumors reached about 4 mm in diameter, they were ablated under supervision of MR diffusion-weighted MRI, sparing the surrounding normal brain tissue. Contrast-enhanced MRI data were obtained before LITT, immediately after and at post-LITT 24 h. The brains were processed for histopathology and stained with hematoxylin and eosin (H&E) for visualizing the extent of the tumor and for major histocompatibility complex (MHC) to identify the human-derived U251 cells. All rats survived the LITT procedure. A ring of contrast enhancement around ablation perimeter was observed immediately after, and also at 24 h. H&E data showed near-complete ablation of the tumors. However, MHC staining showed U251 cells still remaining in the ablation vicinity. These data suggest this model is useful for examining the temporal and spatial development of peri-ablation BBB opening following LITT. Concurrent timing of post-ablation chemotherapy to the development and presence of post-LITT BBB opening may aid in efficient targeting of remaining tumor cells.
EXTH-49. THERAPEUTIC EFFICACY OF ENGINEERED, HYDROGEL ENCAPSULATED BIMODAL MSC IN GLIOBLASTOMA STRATIFIED ON CELL SURFACE RECEPTOR EXPRESSION
Authors: Bhere Deepak , Hugh Choi Sung , van de Donk Pim , Khalsa Jasneet , Hope David , Gortzak Kiki , Kunnummal Amina , Reinshagen Clemens , Ling Huan , Vasdev Neil , Ibn Essayed Walid , Golby Alexandra , Bi Wenya , Lowe Alarice , Wakimoto Hiroaki , Revai Lechtich Esther , Shah Khalid 
Published: November 2019

Abstract
Engineered stem cell therapeutics present a promising therapeutic strategy for glioblastoma (GBM). However, their clinical translation in GBM patients is limited due to lack of mouse models that mimic clinical GBM scenario, dearth of stratification techniques for target cohorts and safety concerns. In this study, we have validated the potential of stratifying therapy responders based on a circulating tumor cell screen and developed a unique “off-the-shelf” cell surface receptor targeted engineered bi-functional mesenchymal stem cell (MSC) for resected GBMs. We created a dual promoter self-inactivating lentiviral vector plasmid encoding death receptor (DR4/5) ligand (DRL), the tumor specific therapeutic agent and the prodrug-converting enzyme, herpes simplex virus-thymidine kinase (HSV-TK) and engineered clinical grade human bone marrow derived MSC to express the bi-modal therapeutic. We show that hyaluronic acid (HA) hydrogel encapsulated bimodal MSC are retained in the tumor resection cavity and have significant therapeutic efficacy in vitro and in vivo in mice bearing patient derived GBM tumors following DR4/5 stratification by circulating tumor cells in the blood and GBM surgical resection. We also show that fate of engineered MSC can be tracked by PET imaging and activation of pro-drug, HSV-TK enhances the therapeutic efficacy of MSC and results in their elimination post-tumor treatment. Our study reveals that local delivery of hydrogel encapsulated engineered MSC has therapeutic benefits; circumvents concerns of bio-distribution, increases on-site retention and permits tumor-selective migration. Based on this data, we are preparing for a first-in-human study of a hydrogel encapsulated engineered allogeneic MSC product, in primary GBM patients.
ANGI-08. AN ANNEXIN A2-REGULATED PHENOTYPIC SHIFT IN GLIOMA
Authors: Matsumoto Yuji , Ichikawa Tomotsugu , Kurozumi Kazuhiko , Otani Yoshihiro , Fujimura Atsushi , Fujii Kentaro , Shimazu Yosuke , Tomita Yusuke , Hattori Yasuhiko , Uneda Atsuhito , Tsuboi Nobushige , Kaneda Keisuke , Makino Keigo , Date Isao 
Published: November 2019

Abstract

BACKGROUND
Malignant glioma has a poor prognosis and is characterized by excessive proliferation, invasion, and angiogenesis. Previously, we established subclones of glioma cell lines with different invasive phenotypes to investigate the mechanisms of invasion in this malignancy. That study revealed annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we investigated the molecular mechanism of the phenotypic shift in glioma that is induced by ANXA2.

METHODS
We identified ANXA2 target genes using microarray analyses of our four established cell lines and RNA-seq data from the IVY Glioblastoma Atlas Project. Co-expression was then confirmed in human glioma cells. Additionally, qRT-PCR, immunoblotting, invasion assays, proliferation assays, and tube formation assays were performed to uncover the specific roles of these angiogenic invasion-related genes. Furthermore, we examined survival times and phenotypic shifts in vivo.

RESULTS
We identified oncostatin M receptor (OSMR) as an ANXA2-target gene using microarray and RNA-seq, and confirmed its expression correlated with ANXA2 in glioma cells. ANXA2-overexpressing glioma cells showed enhanced OSMR expression and STAT3 phosphorylation, while STAT3 knockdown reduced OSMR expression. When ANXA2 was overexpressed in glioma cells, invasion, angiogenesis, proliferation, and epithelial-mesenchymal transition were promoted; however, silencing OSMR attenuated the ANXA2-induced phenotypic shift. In vivo, ANXA2-overexpressing glioma cells shortened the survival time of tumor-bearing mice, whereas OSMR knockdown increased survival times.

CONCLUSIONS
We analyzed genes whose expression was regulated by ANXA2 in glioma using invasive glioma models. Through this analysis, we identified that ANXA2 and OSMR regulate a phenotypic shift, suggesting that OSMR could be a promising target to treat and prevent glioma invasion.
RARE-49. SEX-SPECIFIC SURVIVAL ANALYSIS IDENTIFIES DIFFERENTIAL CLUSTERS OF PROGNOSTIC RELEVANCE IN PATIENTS WITH PRIMARY CNS LYMPHOMA
Authors: Roetzer Thomas , Nenning Karl-Heinz , Furtner Julia , Seebrecht Lukas , Gesperger Johanna , Woehrer Adelheid 
Published: November 2019

Abstract
Sex-specific differences are increasingly recognized in various diseases but have not yet been investigated for patients with primary CNS lymphoma (PCNSL). We collected clinical information and MR-images from 130 patients with PCNSL (66 f/ 64 m). We segmented MR-images into contrast-enhanced tumor, necrosis and edema for volumetric analysis and additionally quantified anti-PCNSL immune response using anti-CD3 staining in 67 cases. Median overall survival was 10 months for females and 8 months for males (p=0.979). Sex-specific Cox-regression analyses implicated age, performance and immunodeficiency as significant prognostic markers in females, whereas only age remained as significant marker in males. We then performed cluster analyses for females (fC) and males (mC) with complete sets of clinical, imaging, and tissue phenotypes (n=55). In females, two main clusters emerged that were mainly driven by clinical performance with fC1 (n=14) featuring patients with better performance (most of whom received MTX) compared to fC2 (n=18; mOS 21 vs 3 months, p< 0.01). fC2 resolved into two subclusters with better outcome for fC2a based on larger enhancing tumor volume and high immune response (mOS 12 vs. 1 months, p< 0.01). In males, two major clusters emerged (16 vs 7 patients, mOS 5 vs 23 months, p=0.414).), which differed mainly according to treatment approach with higher prevalence of MTX-chemotherapy in mC1. Each cluster could be subdivided into 2 subclusters based on differences in clinical performance in mC1, or according to treatment strategy, i.e., combined chemo-radiotherapy vs radiotherapy-only or best supportive care (mOS 49 vs 2 months, p=0.12) in mC2. In summary, we find prognostically relevant sex-specific clusters in patients with PCNSL that implicate differential roles of tumor-related contrast enhancement and immune response in female versus treatment modality in male patients. Initial differences in cluster-defining factors need further validation in independent cohorts but might have implications for differential patient management.
CBMT-08. IN VIVO EVALUATION OF PENTOSE PHOSPHATE PATHWAY ACTIVITY IN ORTHOTOPIC GLIOMA USING HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE
Authors: Batsios Georgios , Viswanath Pavithra , Cao Peng , Taglang Celine , Subramani Elavarasan , Flavell Robert , Larson Peder , Ronen Sabrina 
Published: November 2019

Abstract
The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumor assessment. One intermediate of the pathway is 6-phospho-δ-gluconolactone (6P-δ-GL), which is produced by phosphorylation of δ-gluconolactone. 6P-δ-GL is further metabolized to 6-phospho-gluconate (6PG). The goal of our study was to evaluate, for the first time, whether hyperpolarized (HP) δ-[1-13C]gluconolactone can be used to assess PPP flux and detect the presence of tumor in an orthotopic glioma rat model. Athymic nude rats bearing orthotropic U87 tumors or age-matched tumor-free controls were investigated. HP studies were performed following intravenous injection of HP δ-[1-13C]gluconolactone and metabolic images using a flyback spectral-spatial echo-planar spectroscopic imaging pulse were acquired. The data were processed using in-house Matlab code. 6P-δ-GL and 6-phospho-γ-[1-13C]gluconolactone were observed in all rats ~10 seconds after HP δ-[1-13C]gluconolactone injection, followed ~5 seconds later by production of 6PG observed at 179.3ppm. These data indicate that HP δ-[1-13C]gluconolactone likely crosses the blood-brain barrier, consistent with its transport via glucose transporters, and is rapidly metabolized. Importantly, 6PG was significantly higher in tumor voxels. The ratio of 6PG-to-6P-δ-GL was comparable in normal brain and in normal-appearing contralateral brain of tumor-bearing rats at 0.43±0.09 and 0.45±0.06 respectively (p=0.85), but significant higher in the tumor regions at 0.70±0.11 (p=0.04 and p=0.02 respectively), consistent with the elevated PPP flux that typically occurs in tumor cells. Our results indicate, to our knowledge for the first time, that metabolism of HP δ-[1-13C]gluconolactone can be assessed in the brain and that elevated 6PG production in glioma provides a potential metabolic imaging approach to probe tumor development, recurrence and response to therapy.
CBMT-09. THERAPEUTIC EFFECT OF INDUCTION OF POLYGLUTAMYLATION IN HIGH-DOSE METHOTREXATE THERAPY TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Fujimoto Kenji , Shinojima Naoki , Makino Keishi , Ichimura Koichi , Mukasa Akitake 
Published: November 2019

Abstract

BACKGROUND
Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. Methotrexate (MTX) incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. In this study, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status and evaluated the combined effect of MTX and the drugs which upregulated polyglutamylation of MTX.

METHODS
Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma cell lines were used for in vitro and in vivo experiments. The association of polyglutamylation and the response to MTX with LV rescue was assessed in these cell lines. Histone-deacetylase inhibitor (HDACI) has been reported to induce polyglutamylation by elevating folpolyglutamate synthetase (FPGS) expression, so the effects of HDACIs on polyglutamylation were evaluated. Combined effects of MTX and HDACI were evaluated by cell viability assay and xenograft mouse models.

RESULTS
The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). The combined effect of MTX and HDACI was significantly enhanced in cell viability assay in vitro (p< 0.05), in subcutaneous (p< 0.001) and intracranial tumor xenografts (p< 0.001).

CONCLUSION
These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combined therapy with HD-MTX and HDACIs might represent a promising treatment for HD-MTX resistant intractable PCNSL.
CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS
Authors: Molloy Abigail , Lakhani Aliya , Najac Chloé , Subramani Elavarasan , Marie Gillespie Anne , Pieper Russell O , Viswanath Pavithra , Ronen Sabrina 
Published: November 2019

Abstract
Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.
CBMT-15. MET INHIBITION DRIVES PGC1A DEPENDENT METABOLIC REPROGRAMMING AND ELICITS UNIQUE METABOLIC VULNERABILITIES IN GLIOBLASTOMA
Authors: Zhang Yiru , Nguyen Trang , Zhao Junfei , Shang Enyuan , Torrini Consuelo , Canoll Peter D , Karpel-Massler Georg , Siegelin Markus 
Published: November 2019

Abstract
The receptor kinase, c-MET, has emerged as a target for glioblastoma therapy. However, treatment resistance evolves inevitably. By performing a global metabolite screen with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, we have identified substantial reprogramming of tumor metabolism, involving oxidative phosphorylation and fatty acid oxidation (FAO) with a substantial accumulation of acyl-carnitines accompanied by an increase of PGC1a in response to genetic (shRNA and CRISPR/Cas9) and pharmacological (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-Glucose and U-13C-Glutamine) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species (ROS). Genetic interference with PGC1a rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that CREB regulates the expression of PGC1a in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and beta-oxidation of fatty acids (etomoxir) enhanced the anti-tumor efficacy of c-MET inhibition. Moreover, based on a high-throughput drug screen, we show that gamitrinib along with c-MET inhibition results in synergistic cell death. Finally, utilizing patient-derived xenograft models, we provide evidence that the combination treatments (crizotinib+etomoxir and crizotinib+gamitrinib) were significantly more efficacious than single treatment without induction of toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibitor treatment and identified novel combination therapies that may enhance the therapeutic efficacy of c-MET inhibition.