bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCIDOT-48. EVALUATING THE THERAPEUTIC EFFICACY AND CONVECTION ENHANCED DELIVERY (CED) TOXICITY ANALYSIS OF CDK4/6 INHIBITOR PALBOCICLIB FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Lee Dennis , Maachani Uday , Adeuyan Oluwaseyi , Guadix Sergio , Souweidane Mark 
Published: November 2019

Abstract
DIPG is a devastating, aggressive brain tumor of childhood. No chemotherapeutic agent has so far shown significant clinical efficacy and focal radiation therapy provides only temporary relief. Recent studies on the genomic aberrations of pediatric gliomas have shown that a subset of these tumors harbor focal gains in proteins of the cyclin-dependent kinase (CDK) 4/6 cell cycle pathway. H3.3K27M mutation, associated with >80% of DIPGs, has also been associated with epigenetic silencing of p16 tumor suppressor, an important effector in regulating CDK4/6 pathway. In this study, we characterized and confirmed through immunoblot analysis that proteins involved in CDK 4/6 pathway, including Rb1, are intact in multiple patient derived DIPG (SU-DIPG-IV, SU-DIPG-XIII, SU-DIPG-XVIII, SF8628) and wild type (SF9428) cell lines. Expression of p16 was decreased or undetectable in DIPG cells compared to normal astrocytes. In addition, pharmacologic inhibition of CDK4/6 with palbociclib showed dose dependent reduction in DIPG cell proliferation with IC50 ranging from 5.42uM to 21.35uM between different cell lines. However, major problems of palbociclib are that it does not readily cross the blood-brain-barrier (BBB) and has major systematic toxicities, such as myelosuppression, which limits oral dosing. One solution to overcome the BBB is convection enhanced delivery (CED) which is a form of local delivery that bypasses the BBB by placement of small diameter catheters directly into the brain tumor. With this approach, high regional drug concentration can be achieved with negligible systemic toxicity. In this study, we also observed no significant short- or long-term neurotoxicity of palbociclib delivered via CED in a mouse model. We hypothesize that the CDK4/6 cell cycle pathway has an important role in DIPG tumorigenesis and progression and that existing therapies targeting these pathways, which are already in clinical use for other cancers, can be rapidly repurposed for the treatment of DIPG through CED.
SCIDOT-52. IN SITU DELIVERY OF TUMOR TREATING FIELDS THERAPY IN GLIOBLASTOMA PATIENTS
Authors: Arle Jeffrey , Wong Eric , Korshoej Anders , Dokos Socrates , Bomzon Ze’ev , Carlson Kristen 
Published: November 2019

Abstract
The efficacy of Tumor-Treating Fields (TTFields) rests on the result of a large-scale clinical trial that demonstrated an increase in the survival of newly diagnosed glioblastoma patients when combined with temozolomide chemotherapy. Overall survival now extends to over 60 months in some of our patients when dexamethasone, which we suspected of interference with TTFields effects, is replaced with celecoxib to control tumor-associated inflammation. The transcranial method of delivering TTFields has not changed in light of ongoing advances in deep brain stimulation (DBS) and transcranial electric stimulation (TES), notably that the resistivity of the skull is the principle obstacle to placing therapeutic electric field strength of 2 V/cm into target tumor sites and variation in skull thickness is the main difference in TES efficiency across individuals. Realistic human head finite element modeling (FEM) predicted that surgical craniectomy beneath TTFields’ electrodes would enhance field strength at target tumor sites. Here we show that 2 V/cm can be reliably delivered to tumor sites using minimally-invasive DBS cylindrical leads or ribbon electrode arrays, pre- or post-resection. Two objections arise to the in situ method: 1) Will TTFields stimulate axons in situ? 2) Will field strength exceed safety limits for cell damage? Neural stimulation modeling and experiments show that TTFields’ frequency of 200 kHz, 1–3 orders of magnitude higher than ion channel time constants, is too high to stimulate them. Furthermore, 2 V/cm is well below cell damage limits of 700 V/mm. Thus we propose a new delivery method to improve tumor control in glioblastoma patients and to provide valuable information on TTFields’ effects via cell studies using in situ electric fields at 200 kHz.
RARE-50. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA – OUTCOMES IN THE ‘HAEMATOLOGY ERA’
Authors: Kumar Siddhant , Islim Abdurrahman , Smith Jeffrey , Haylock Brian , Shenoy Aditya , Husband David , Mills Samantha , Brodbelt Andrew , Chavredakis Emmanuel , Lawson David , Jenkinson Michael 
Published: November 2019

Abstract

BACKGROUND
Primary CNS lymphoma (PCNSL) requires a biopsy for diagnosis. Administration of corticosteroids can lead to inconclusive results and delay diagnosis. The aim of this study was to compare outcomes of patients treated under haematology compared to radiation oncologists.

METHODS
Retrospective case review of patients treated under radiation oncology (2006–2010) and haematology (2011–2016).

RESULTS
121 cases were identified (median age 63 years; range 19–84). Median WHO performance status (PS) was 1. Fourteen patients (11.6%) required repeat biopsy. 10 patients were managed palliatively due to poor PS. 67 cases were managed under haematology. Median symptom duration was 28 days (range 2–540). Median time from MRI to diagnosis was 18 days (range 6–232). 66 patients received chemotherapy, 1 received radiotherapy. Median overall survival (OS) was 8 months (95%CI:0.7–15.3), 5-year OS was 22.4%. 44 cases were managed under radiation oncology. Median symptom duration was 28 days (range 2–365). Median time from MRI to diagnosis was 16 days (range 6–309). 34 patients received radiotherapy first-line, 10 received chemotherapy. Median OS was 7 months (95%CI:0–21.5), 5-year OS was 15.9%. Multivariate analysis demonstrated PS (HR 2.02 (95%CI: 1.08–3.76)) and symptom duration (HR 0.63 (95%CI: 0.41–0.96)) to be significant prognostic indicators for OS.

CONCLUSION
The outcomes from the ‘haematology era’ are similar to those achieved by radiation oncologists. Delay in diagnosis leads to worse outcomes and highlights the ongoing need to streamline the patient pathway to improve outcomes.
ANGI-11. SEX DIFFERENCES IN IMAGING-BASED ASSESSMENT OF GLIOBLASTOMA INVASION
Authors: Christine Massey Susan , Hawkins-Daarud Andrea , Jackson Pamela , Grove Rebecca , Bakken Katrina , He Lihong , Mladek Ann , Stokes Ashley , Gonzalez Ashlyn , Nespodzany Ashley , Eschbacher Jenny , Baxter Leslie , Smith Kris , Nakaji Peter , McGee Samuel , Bendok Bernard , Burns Terence , Sarkaria Jann , Hu Leland , Swanson Kristin 
Published: November 2019

Abstract

INTRODUCTION
Neuroimaging dogma for glioblastoma asserts that hyperintensity on T1Gd MRI reveals the bulk of the tumor, while T2/FLAIR signal indicates edema. However, it is unclear whether this edema results from immune response or increased tumor cells. Further, one significant driver of the known sex differences in glioblastoma may be differences in immune response, due to the X-linkage of many immune genes. Based on this, we hypothesized that assumptions regarding tumor cellularity in T2/FLAIR images should be tailored to the biological sex of the patient.

METHODS
Using a retrospective cohort of 18 primary glioblastoma patients receiving multiple image-localized biopsies (82 total) and standard MRI, we assessed: distance of biopsy from T1Gd and T2 areas; a pathologist’s score of percent tumor cell density; and an imaging-based invasion metric, D/ρ. This metric is derived from the biomathematical Proliferation-Invasion model of glioma growth, which features two parameters, net growth rate (ρ) and net invasion rate (D). Their ratio D/ρ is related to degree of invasion, and is estimated from volumetric measurements of MRI abnormalities. Additionally, 25 patient-derived xenograft models implanted in females were grown until moribund, at which point brains were excised and stained for DAPI (to show all cells) and Lamin (to highlight tumor cells). Image processing of lamin-stained sections defines contours of intensity correlating with cell density.

RESULTS
Outside both the T1Gd and T2 region, male patient biopsies had higher tumor cell densities than females. Males also tended to have higher invasion metrics. Although each set derived from different patients, preclinical metrics of invasion were positively correlated with clinical invasion in females but negatively correlated in males.

CONCLUSION
Our preliminary finding that cell distribution patterns correlate with imaging metrics differently between the sexes supports the hypothesis that the degree of tumor cell density represented on certain MRI sequences may be sex-specific.
CBMT-01. ALANINE FUELS ENERGY METABOLISM OF GLIOBLASTOMA CELLS
Authors: Ijare Omkar , Baskin David , Pichumani Kumar 
Published: November 2019

Abstract
Despite available aggressive treatment options, glioblastoma multiforme (GBM) has a median survival of 16 months indicating an urgent unmet need to develop new therapeutic strategies. Earlier, we have demonstrated that both glucose and acetate are the two major nutrients leading to synthesis of approximately ~60% acetyl-CoA in the brain tumors. Therefore, there must be other nutrients that may contribute to bioenergetic needs of highly proliferative GBM cells. Alanine is one of the non-essential amino acids (NEAA) that is constantly produced in cancer cells through Warburg glycolysis and its role in cancer metabolism is not well understood. Recently, it has been shown that alanine produced by pancreatic stellar cells contributed to the energy metabolism in pancreatic cancer cells. However, it is not known whether GBM can use alanine as an energy source. Here, we test whether GBM cells have the ability to metabolize alanine as a fuel to meet its increased energy requirements. Patient-derived GBM cells were cultured with 2.0 mM [3-13C]alanine for the final 24 hours, harvested in 50% methanol, snap-frozen in liquid N2, freeze-thaw cycle 3 times and lysates were stored at -80 °C. Derivatized material from the frozen lysates were used for GC-MS analysis to determine carbon mass isotopomer distribution (MID) of various glycolytic and TCA cycle intermediates. Our results indicated that [3-13C]alanine entered the GBM cells and produced [3-13C]lactate via pyruvate. Also, alanine-derived [3-13C]pyruvate led to the generation of [2-13C]acetyl-CoA, which entered TCA cycle and produced M+1 13C isotopomers of citrate, glutamate, malate and aspartate. MID showed the following 13C enrichment (M+1) values: citrate, 6.9 % ± 0.3%; glutamate, 4.4% ± 0.3%; malate, 2.1% ± 0.6%; 2.1% ± 0.5%. This preliminary data shows that GBM cells are capable of utilizing alanine to generate energy and produce precursors for biomolecular synthesis.
CBMT-02. UP-REGULATION OF Γ-GLUTAMYL-TRANSFERASE CAN BE USED TO IMAGE GLIOBLASTOMA USING HYPERPOLARIZED Γ-GLUTAMYL-[1-13C]GLYCINE MRS
Authors: Batsios Georgios , Najac Chloe , Cao Peng , Viswanath Pavithra , Subramani Elavarasan , Saito Yutaro , Marie Gillespie Anne , Yoshihara Hikari , Larson Peder , Sando Shinsuke , Ronen Sabrina 
Published: November 2019

Abstract
γ-glutamyl-transferase (GGT) is a key enzyme in the γ-glutamyl cycle, which regulates glutathione homeostasis. The enzyme is localized on the outer cell membrane and cleaves glutathione to glutamate and cysteinylglycine. As such, it facilitates uptake of the amino acids essential for intracellular synthesis of glutathione (GSH), which is the major thiol anti-oxidant. GGT is upregulated in glioblastoma, but remains low in normal brain. It is therefore an attractive molecular imaging target for specific detection of glioblastoma. The goal of our study was therefore to assess for the first time the value of hyperpolarized (HP) γ-glutamyl-[1-13C]glycine (γ-Glu-[1-13C]Gly) for imaging glioblastoma in orthotopic tumor-bearing rats. Athymic nude rats with U87 glioblastoma tumors or tumor-free controls were investigated. First, we confirmed that GGT expression was significantly higher in U87 tumors compared to normal rat brain tissue. GSH levels were also higher. Imaging studies were then performed by injecting HP γ-Glu-[1-13C]Gly and acquiring dynamic 13C MR spectra using a flyback spectral-spatial slab sequence on a preclinical Bruker 3T MR system. The dynamic data were analyzed by measuring the signal-to-noise (SNR) ratios of the substrate (γ-Glu-[1-13C]Gly) and the product ([1-13C]Glycine). Comparison of control and tumor-bearing rats showed no statistically significant difference in the SNR of the substrate. In contrast, the SNR of the product demonstrated a significantly higher level of HP [1-13C]Glycine in the tumor-bearing rats compared to controls. Consistent with the higher levels of HP [1-13C]Glycine, the [1-13C]Gly-to-γ-Glu-[1-13C]Glycine ratio was also significantly higher in tumor-bearing animals relative to controls (0.046±0.004 vs 0.021±0.008 respectively; p=0.03). Further studies are needed to assess the generality of our findings. Nonetheless, this study demonstrates for the first time the feasibility of using γ-Glu-[1-13C]Gly to monitor GGT activity and thus could serve as a new approach for monitoring the presence of tumor.
CBMT-03. EVALUATION OF PET TRACERS TO DIFFERENTIATE IDH1 MUTANT GBM
Authors: Molotkov Andrei , Mela Angeliki , Canoll Peter D , Mintz Akiva 
Published: November 2019

Abstract

OBJECTIVE
PET/CT offers the unique potential to noninvasively evaluate biomarker expression and aberrant metabolism. 18F-FDG has driven PET/CT to the forefront of cancer imaging, as altered glucose metabolism is a hallmark of oncogenesis. However, 18F-FDG is suboptimal for GBM due to high physiologic uptake in normal brain. The development of alternative tracers has reignited the field of PET/CT in GBM and offers hope for diagnosis and molecular staging in GBM. We hypothesize that fundamental differences in metabolism and oncogene expression present in IDH1 mutatant gliomas can be shown using PET imaging, as has been suggested in some correlative clinical studies. Our objective was therefore to establish a causal link between IDH1 mutation in GBM and uptake of targeted PET tracers in a unique proneural GBM transgenic model characterized by p53, IDH1 mutations and PDGF expression.

METHODS
We examined the uptake of 3 blood-brain-barrier (BBB) penetrant tracers that have been used in GBM: (a) 18F-FDG, a surrogate for increased glycolysis; (b) 18F-Fluciclovine, an amino acid derivative transported into cells through the energy-independent L-type amino acid transporter (LAT) system and is approved by the FDA for prostate cancer; and (c) 11C-ER176, a tracer that binds the TSPO receptor that is generally expressed on activated microglia as well as GBM.

RESULTS
We did not observe significant differences in 18F-FDG uptake between wt and IDH mutant GBM cells. However, we found that IDH mutant GBM cells demonstrated significantly increased 18F-Fluciclovine (47%) and 11C-ER176 (53%) versus IDH wt cells.

CONCLUSION
We have established a causal link between IDH mutation status and uptake of (a) 18F-Fluciclovine, a promising FDA approved PET tracer and (b) 11C-ER176, a second generation TSPO ligand. Thus, we are performing further studies in orthotopic syngeneic GBM models to determine if PET imaging can non-invasively demonstrate molecular characterization and therapeutic stratification in glioma.
CBMT-05. GENETIC AND EPIGENETIC MECHANISMS REGULATING SCD INHIBITOR SENSITIVITY IN GLIOBLASTOMA
Authors: Oatman Nicole , Dasgupta Nupur , Dasgupta Biplab , Choi Kwangmin , Gawali Mruniya , Gupta Nishtha , Parameswaran Sreeja , Lawler Sean , Brennan Cameron , Wu Jianqiang , Sallans Larry , Desai Pankaj , Weirauch Matthew , Komurov Kakajan , Dasgupta Biplab 
Published: November 2019

Abstract
A status-quo in targeted cancer therapy is that out of the thousands of somatic alterations found in a cancer cell, alterations only in driver genes determine therapeutic strategy. Despite unimpressive results of some driver-targeted therapies, and given that the majority of genomic alterations in cancer are not ‘drivers’, but ‘passengers’ / bystander alterations, it remains underappreciated whether targeting built-in vulnerabilities imposed by passenger gene alterations may provide therapeutic value. The tumor suppressor PTEN undergoes widespread functional inactivation including deletion in human cancer. PTEN deletion occurs frequently in GBM, sometimes as part of the 10q loss or chromosome 10 monosomy. We discovered that several genes including Stearoyl Co-A Desaturase, SCD (10q24.31), located 12 MB telomeric to PTEN is frequently co-deleted hemizygously and unintentionally in PTEN-deleted cancers. Strikingly, in a subset of GBM, SCD was also epigenetically silenced. A combination of SCD deletion and methylation resulted in two molecular subgroups – one that expressed SCD, and another that showed little or no detectable SCD. SCD, is an integral membrane protein of the endoplasmic reticulum and converts saturated fatty acids to monounsaturated fatty acids (Oleic and palmitoleic acids) that are critical for membrane fluidity and function, and thus SCD is generally overexpressed in most cancers. We show that SCD expressing lines are highly sensitive to multiple SCD inhibitors, while non-expressors are resistant. Despite modest BBB penetration, one SCD inhibitor was remarkably efficient in blocking intracranial tumor growth. SCD is an oxygen-dependent enzyme. We show that SCD retains significant enzymatic activity even in highly hypoxic conditions. Finally, through RNAseq, functional proteomics and ATACseq, we demonstrate an evolutionarily conserved mechanism of acquired resistance to SCD inhibitor through drug-induced acute phase signaling response in multiple SCD expressing cancers.
CBMT-25. THE KLF4K409Q MUTATION IN MENINGIOMA IMPAIRS HIF-1Α DEGRADATION AND CAN BE HARNESSED FOR TARGETED THERAPY
Authors: von Spreckelsen Niklas , Waldt Natalie , Poetschke Rebecca , Kesseler Christoph , Dohmen Hildegard , Jiao Hui-Ke , Nemeth Attila , Deckert Martina , Angenstein Frank , Krischek Boris , Stavrinou Pantelis , Timmer Marco , Remke Marc , Kirches Elmar , Goldbrunner Roland , Chiocca Ennio , Huettelmaier Stefan , Acker Till , Mawrin Christian 
Published: November 2019

Abstract
Recently, several Non-NF2 driver mutations (KLF4, TRAF7, SMO, AKT1E17K) in meningioma have been identified. While they have been shown to correlate with certain pathological subtypes and locations, the clinical impact and repercussions on cellular pathways have largely remained elusive. Through analysis of clinical, pathological and preoperative imaging data of 96 patients and sequencing of the corresponding 96 tumor samples for the Krueppel like factor 4-K409Q mutation (KLF4K409Q) we present evidence that the KLF4K409Q tumors harbour an increased risk for peritumoral brain edema (PTBE) and can be predicted with the edema-index, a simple tool based on preoperative imaging. Further analysis involving RNA-sequencing of a matched subset of 7 KLF4K409Q and 10 KLF4-wildtype (wt) tumors revealed a significant shift of gene expression and the upregulation of hypoxia driven pathways, including VEGF levels, in KLF4K409Q tumors. On the cellular level, we go on to show that the KLF4K409Q mutation results in an increased KLF-4 stability as well as the inhibition of hydroxylation dependent degradation of HIF1-α and a significant increase of VEGF expression under hypoxic conditions. Finally, we demonstrate that this upregulation of VEGF in KLF4K409Q cells can be inhibited by targeting the mammalian target of rapamycin (mTor) with Temsirolimus. In summary we show that the KLF4K409Q mutation in meningioma has highly relevant repercussions in both, the biological and clinical context and can be harnessed for targeted therapy.
CBMT-28. FATTY ACID OXIDATION PROVIDES METABOLIC PLASTICITY TO MAINTAIN GROWTH IN THE DYNAMIC MICROENVIRONMENT OF GLIOBLASTOMA
Authors: Kant Shiva , Kesarwani Pravin , Prabhu Antony , Graham Stewart , Buelow Katie , Nakano Ichiro , Chinnaiyan Prakash 
Published: November 2019

Abstract
Glioblastoma represents an aggressive, primary brain tumor with limited treatment options. Despite advances in molecularly characterizing glioblastoma, metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analyses coupling global metabolomic and gene expression profiling identified alterations in fatty acid β-oxidation (FAO) as a key metabolic node differentiating glioblastoma from low-grade astrocytoma, which was defined by an accumulation of acylcarnitines. Metabolic heterogeneity was observed within glioblastoma that could further define tumors as FAO ‘high’ and ‘low’, which were enriched with mesenchymal and proneural subtypes of glioblastoma, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models, with the majority of baseline mitochondrial oxygen consumption being a result of enhanced FAO in these cells. The biologic consequence of enhanced FAO in glioblastoma is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A/cAMP-dependent autocrine manner in nutrient favorable conditions while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Accordingly, inhibiting FAO alone in glioblastoma cells with etomoxir only led to modest anti-proliferative activity and minimal cytotoxicity. However, rational combinatorial strategies designed to target the dynamic roles FAO plays in gliomagenesis resulted in metabolic synthetic lethality in glioblastoma. Specifically, dual targeting of FAO (etomoxir) and glycolysis (2DG) resulted in robust energetic stress, necroptosis mediated cell death, and a significant improvement in survival in an orthotopic glioblastoma mouse model. In summary, we identified FAO as a dominant metabolic node in glioblastoma that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in glioblastoma.
CBMT-38. THERAPEUTIC INHIBITION OF THE SPLICEOSOME IN GLIOBLASTOMA: CHANGES FORM MINOR TO MAJOR
Authors: Bonifert Tobias , Arora Sonali , Fitzgibbon Matthew , Paddison Patrick 
Published: November 2019

Abstract
Chemical or genetic perturbation of the spliceosome function may represent a therapeutic opportunity for Glioblastoma multiforme (GBM) and other cancers. We and others have shown that oncogenic MYC activity causes spliceosome vulnerability and leads to deficits in 3’ splice site recognition upon spliceosome perturbation. Several spliceosome inhibitors in pre-clinical development and in clinical trials target the U2 snRNP subcomplex SF3B, which is essential for 3’ splice site recognition. We showed that knockdown of one of its subunits, PHF5A, causes GBM-specific changes in splicing, including increases in exon skipping, intron retention and activation of alternative 3’ and 5’ splice sites. However, in depth analysis of these events revealed they are disproportionately enriched for “minor” introns. This class of ~800 introns is specifically excised by an alternative splicing pathway which involves the U12-dependent spliceosome. Remarkably, we provide evidence that inhibition of PHF5A in GBM stem-like cells causes increased retention of most minor introns, as well as activation of cryptic and alternative U2 snRNP-dependent splicing sites. We further demonstrate that components of the U12 snRNP complex are differentially required for GSC-specific viability. Our results suggest that regulation of the splicing of U12-type introns may be critically important for GBM tumor cell viability.