bluuebunny/crossref_metadata_2025_split huggingface dataset:
CBMT-17. DEFECTIVE QKI-DEPENDENT LIPID METABOLISM INDUCES GENOMIC INSTABILITY AND SENSITIZES GLIOBLASTOMA TO IMMUNOTHERAPY
Authors: Shingu Takashi , Hu Jian 
Published: November 2019

Abstract
Despite transformative effects on the therapy of cancers such as melanoma and lung adenocarcinoma, blockade of the T cell immune checkpoints has generated limited impact on glioblastoma. Identifying genetic/genomic alterations that could potentially sensitize the patients to immunotherapy will significantly improve the efficacy of immunotherapy on glioblastoma patients. As part of our effort to identify novel glioma suppressors that affect the interaction of GSCs with their microenvironment, we discovered that the RNA-binding protein Quaking (QKI) is a key regulator of cellular endocytosis. QKI is mutated or deleted in ~34% of human glioblastomas. Supporting QKI’s tumor suppresser function, 92% of the Nestin-CreERT2;QkiL/L;PtenL/L;p53L/L mice developed glioblastoma with a median survival of 105 days, however, the Nestin-CreERT2;PtenL/L;p53L/L mice did not develop any glioma up to a year. Mechanistically, QKI regulates the RNA stability and alternative splicing of numerous protein and lipid components of endolysosomes, particularly the unsaturated fatty acids (UFAs). Functionally, deletion of Qki and inhibition of UFA biosynthesis both decrease endolysosome-mediated receptor degradation, thereby enriching receptors on the cytoplasmic membrane (e.g., Frizzled and Notch1) that are essential for maintaining stemness. This enrichment of receptor signaling enables GSCs to cope with the low ligand levels during their invasion. On the other hand, lower lysosomal activity induced by Qki deletion and UFA loss led to defective mitophagy. We also found that insufficient UFAs in mitochondrial membrane significantly compromised mitochondrial membrane integrity and function. These two mechanisms concomitantly led to accumulation of damaged mitochondria and higher levels of reactive oxygen species (ROS), and consequently genomic instability. Lastly, we found that the higher level of genomic instability induced by Qki loss rendered cells more sensitive to anti-CTLA4 and anti-PD1 antibodies. Taken together, our data suggest that Qki/UFA loss-induced endolysosomal and mitochondrial defects promote gliomagenesis yet render cells vulnerabilities that could be harnessed for therapeutic purposes.
CBMT-24. CHARACTERIZATION OF PRIMARY CILIUM IN RECURRENT GLIOBLASTOMA: IMPLICATIONS FOR NEW THERAPEUTIC TARGETS
Authors: Stumpo Vittorio , Marappian Aruljothi , Giorgio D’Alessandris Quintino , Pacioni Simone , Di Bonaventura Rina , Ebbert Lara , Giordano Martina , Caccavella Valerio , Olivi Alessandro , Laura Falchetti Maria , Ricci-Vitiani Lucia , Pallini Roberto , Gopalakrishnan Jay 
Published: November 2019

Abstract

INTRODUCTION
Primary cilium is a highly conserved, dynamic cellular organelle which plays several roles in embryonic development, intracellular signaling, and cell cycle. Structural alterations of primary cilium have been described in human gliomas including glioblastoma (GBM), however, its actual role in pathogenesis and treatment resistance of these tumors is largely unknown.

METHODS
We investigated cilium morphology and expression of cilium-related genes in human glioma of various WHO grade and in couples of patient-derived glioma stem-like cells (GSCs) that were established from the very same GBM at first diagnosis and at recurrence. Immunohistochemistry with anti-Arl13b antibody was used to assess cilium morphology. The expression levels of genes involved in ciliary disassembly complex (CDC) were analyzed by quantitative real-time PCR, using neural progenitor cells (NPCs) as control. Lastly, we assessed 3 GSC cultures that were treated with a drug inhibiting cilia disassembly (CCB-Cil).

RESULTS
Anaplastic oligodendroglioma and proneural GBM showed the highest percentage of ciliated cells. In GBM, we found the highest percentage of fragmented cilia. GSCs derived from newly diagnosed GBMs displayed lower percentages of ciliated cells than those derived from recurrent GBMs (20% vs 70%). Morphological analysis indicated that GSCs from recurrent GBM show cilia with extremely various morphology compared with GSCs from newly diagnosed GBM and NPCs. Gene analysis showed reduced expression of CDC-related genes in GSCs from newly diagnosed GBM with respect to those from recurrent GBMs. CCB-Cil treatment determined a global reduction of CDC-related genes, increased expression of differentiation markers (GFAP), and reduction of stemness markers (SOX2).

CONCLUSIONS
The increased percentage of ciliated cells in GSCs from recurrent GBM may be related to a compensatory response of CDC and to an accelerated ciliary turnover. Blocking cilia disassembly reduces stemness features and induces differentiation in GSCs, suggesting that this approach could represent a promising strategy for targeting GBM.
CBMT-27. ABERRANT AMINO ACID METABOLISM EXPOSE NOVEL FUNCTIONAL VULNERABILITIES IN GLIOBLASTOMA
Authors: Prabhu Antony , Guastella Anthony , Kant Shiva , Kesarwani Pravin , Nakano Ichiro , Chinnaiyan Prakash 
Published: November 2019

Abstract
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 aberrant amino acid (AA) metabolism as a central node in glioblastoma. This metabolic phenotype was recapitulated in preclinical models and through a series of investigations designed to determine the biologic consequence of individual AA, we identified branched chain AA (BCAA) and glutamine as the only indispensable AA in glioblastoma, serving as the sole source of nucleotide pools and glutathione, respectively. Although molecularly and/or chemically perturbing these pathways resulted in cytotoxicity in glioblastoma, normal astrocytes demonstrated a similar response, suggesting therapeutic limitations in targeting these core metabolic pathways in cancer. As the glioblastoma microenvironment typically represents a nutrient-deprived state, we went on to determine the capacity of these cells to adapt to AA restricted conditions by only providing these cells with the above-identified indispensable AA. Intriguingly, glioblastoma cells had the unique ability to revert a state of metabolic dormancy. In addition to triggering a reversible proliferative arrest, this dormant phenotype displayed a near-complete shutdown of glycolysis that allowed these cells to adapt and maintain survival in glucose-deprived conditions and elicited profound resistance to ionizing radiation. Studies designed to systemically understand molecular underpinnings driving this unique metabolically dormant state uncovered a functional reliance upon mTOR/p21 signaling to maintain proliferative arrest in nutrient unfavorable conditions. Consistent with these findings, p21 expression was differentially expressed in the perinecrotic core of glioblastoma when compared to the peripheral edge in patient samples. Targeting this novel functional vulnerability through p21 inhibition, thereby, ‘forcing’ proliferation of these cells in nutrient unfavorable conditions, led to robust cytotoxicity specific to dormant cells and enhanced radiation response. Targeting functional vulnerabilities in otherwise therapeutically resistant cells represents a promising clinical strategy in glioblastoma.
CBMT-31. HDAC INHIBITION DIMINISHES THE GROWTH OF ENDOGENOUS IDH MUTANT GLIOMAS
Authors: Elahi Lubayna , Garrett Matthew , Guo Lea , Condro Michael , Kawaguchi Riki , Mehta Shwetal , Lai Albert , Pope Whitney , Kornblum Harley 
Published: November 2019

Abstract
Histone deacetylase inhibitors (HDACi’s) have emerged as a promising class of drugs for treatment of malignancies such as glioblastoma (GBM). Several studies have demonstrated the anti-tumor property of HDACi’s against GBM in both in vitro and in vivo experiments. Nonetheless, in clinical trials, HDACi only marginally increased overall survival of patients with GBM. The mixed results of trials with HDACi’s in glioma have prompted us to hypothesize that improved selection of patients by tumor characteristics could enhance the efficacy of therapy. We specifically tested the effects of valproic acid (VPA), a HDACi and an antiepileptic drug against IDH mutant gliomas. We have previously demonstrated that our IDH mutant glioma cell lines have gene expression and methylation patterns highly similar to IDH mutant tumors in situ. Mutant IDH1 alters the epigenetic landscape of gliomas leading to the hypermethylation phenotype and transcriptional repression of genes. This repression of genes may contribute to tumorigenesis and progression of IDH mutant gliomas. We found that VPA inhibits the growth of patient-derived IDH1 mutant glioma lines. In addition, RNA sequencing analysis of vehicle and VPA-treated IDH1 mutant glioma cells showed de-repression of several genes previously shown to be downregulated in IDH1 mutant glioma cell lines. We also treated cells with another HDACi LBH589 and found that both VPA and LBH589 upregulates similar gene sets suggesting that HDAC inhibition promotes de-repression of previously repressed genes. Ongoing studies are aimed at determining the molecular mechanism by which VPA regulates the growth of IDH1 mutant tumors.
CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO
Authors: Viswanath Pavithra , Batsios Georgios , Marie Gillespie Anne , Pieper Russell O , Ronen Sabrina 
Published: November 2019

Abstract
Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.
CBMT-46. MICRORNA-206 ATTENUATES GLIOMA CELL PROLIFERATION, MIGRATION, AND INVASION BY BLOCKING THE WNT/β-CATENIN PATHWAY VIA DIRECT TARGETING OF FRIZZLED 7
Authors: Wang Yingyi , Zhou Fengqi , Zhao Chunsheng 
Published: November 2019

Abstract
Glioma is one of the most frequent primary malignant brain tumours in adults and accumulating evidence has shown that microRNAs (miRNAs) are associated with various types of tumours, including glioma. It is essential to acquire a better understanding of the roles and mechanisms of miRNAs in WNT-driven glioblastoma (GBM). Here, we report that miR-206 inhibited the WNT/β-catenin pathway by directly targeting Frizzled 7 (FZD7) and functioned as a tumour-suppressor in glioma. The expression of miR-206 in human samples and glioma cells was assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), and histological analysis. Cell Counting Kit-8 (CCK-8), colony formation, EdU, flow cytometry, wound healing, transwell invasion, and three-dimensional migration were performed to observe cellular proliferation, migration, and invasion in vitro. The effects of miR-206 in vivo were investigated using a xenograft nude mouse model. miR-206 expression was significantly downregulated in glioma specimens. FZD7 was confirmed as a direct target of miR-206. GBM cell proliferation, migration, and invasion were blocked by restoring the expression of miR-206. Moreover, intracranial glioma models demonstrated an inhibitory effect of miR-206 on intracranial glioma tumour growth. Our results suggested that miR-206 plays a key role in blocking the WNT/β-catenin signalling pathway by suppressing FZD7 and provides a prospective therapeutic strategy for the treatment of malignant glioma and other WNT-driven tumours.
CBMT-47. MODULATION OF NAD PATHWAYS AS A THERAPEUTIC STRATEGY FOR TARGETING IDH MUTANT GLIOMA
Authors: Miller Julie , Nagashima Hiroaki , Fink Alexandria , Tateishi Kensuke , Wakimoto Hiroaki , Banagis Jack , Cahill Daniel 
Published: November 2019

Abstract

BACKGROUND
IDH mutant tumors exhibit an altered metabolic state which may be exploited for use as a novel therapeutic approach. Our previous work has shown the IDH mutant cancer survival is dependent on the biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), for the production of nicotinamide adenine (NAD). Inhibition of NAMPT activity (NAMPTi) efficiently targets IDH mutant cells. NAD steady-state is also influenced by consumptive processes that utilize NAD as a coenzyme, including Sirtuin (SIRT) signaling. To avoid concerns surrounding NAMPT inhibitor toxicity at high doses, we sought to investigate whether modulation of SIRT activity can effectively target IDH mutant cells.

METHODS
IDH1 mutant cancer cells and patient-derived glioma lines were engineered for loss of SIRT gene expression using CRISPR/Cas9 gene editing or SIRT1 overexpression using a tetracycline-inducible expression system. The effect of silenced or enhanced SIRT1 activity was then assessed in IDH1 mutant cells alone or in combination with NAMPT inhibitors.

RESULTS
Loss of SIRT1 expression, but not other SIRT family members, confers resistance to NAMPT inhibition in IDH1 mutant cells. Consistent with the hypothesis that SIRT1 is a major consumer of NAD, we observed a significantly smaller decline in NAD when SIRT1 is deleted. In agreement with these findings, when SIRT1 activity is enhanced from baseline by tetracycline-mediated induction of SIRT1 expression, IDH mutant cell growth is slowed. Further, overexpression of SIRT1 leads to decreased cell viability and enhanced NAD depletion when induced in combination with NAMPTi.

CONCLUSIONS
IDH mutant tumors are vulnerable to NAD depletion. Our results show that this metabolic liability can be targeted by a combination of enhanced NAD consumption via SIRT1 activation and inhibition of NAD synthesis. Importantly, compounds to enhance SIRT1 activity are relatively non-toxic and in development for aging and neurologic disease, allowing potential for rapid translation to an IDH mutant-directed treatment.
CSIG-03. STAT3-BASED PATIENT STRATIFICATION IN PRECISION NEURO-ONCOLOGY
Authors: Tan Melanie , Sandanaraj Edwin , Chong Yuk-Kien , Lim See-Wee , Koh Lynnette , Ng Wai-Hoe , Tan Nguan-Soon , Tan Patrick , Ang Beng-Ti , Tang Carol 
Published: November 2019

Abstract
Glioblastoma (GBM) displays both spatial and temporal heterogeneity, whereupon mesenchymal tumors fare more poorly than the proneural molecular subtype. STAT3 was selected because its activation preceeds the proneural-mesenchymal transition. We first defined a STAT3 gene signature that stratified GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigated STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. In addition, we elucidated the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells, allowing us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. As such, we show that dual inhibition of IGF-1R and STAT3 sensitized STAT3-low cells and improved survival in mice. Our study emphasizes the clinical implications of molecular subtype switching and demonstrates the importance of serially profiling GBM tumors upon recurrence so as to facilitate effective therapy.
CSIG-24. GABP LINKS AMPK SIGNALING TO TERT REGULATION IN A TERT PROMOTER MUTATION DEPENDENT MANNER
Authors: McKinney Andrew , Amen Alexandra , Stevers Nicholas , Costello Joseph 
Published: November 2019

Abstract
Over 90% of human tumors achieve immortality by reactivating telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. Two mutually exclusive, heterozygous mutations that activate the TERT promoter (TERTp) occur in a wide range of cancers including ~80% of glioblastomas (GBM). The mutations and TERTp activation enable cells to avoid replicative senescence and continue to divide beyond the normal limits on cellular lifespan, thus becoming immortal. Our lab has demonstrated that each mutation creates a novel E26-transformation specific binding site that allows the tetrameric form of the GA-binding protein GABP to bind and aberrantly activate the mutant TERTp. We further showed that reducing a tetramer-forming subunit of GABP, the GABPB1L transactivating subunit, reverses cellular immortality in vitro and reduces tumor growth in vivo. Beyond GABP, little is known about pathways that contribute to immortality via activation of the mutant TERTp. The heterotrimeric 5’ AMP-activated protein kinase (AMPK) complex is activated in human GBM compared to normal brain, and was previously implicated in regulating GABP expression. Here, we have determined that AMPK inhibition decreases transcription of both subunits of the tetrameric GABP complex (GABPA and GABPB1L) in GBM cells, and is sufficient to reduce TERT expression and telomerase activity in a TERT promoter mutation dependent manner. Together, these data suggest a novel and targetable connection between the AMPK signaling axis, telomerase activity and potentially tumor cell immortality.
CSIG-30. miR-146a INHIBITS TUMORIGENESIS AND INDUCES TEMOZOLOMIDE SENSITIVITY VIA AFFECTING CANCER STEM CELL PROPERTIES IN GBM
Authors: Cui Tiantian , Hlavin Bell Erica , McElroy Joseph , Liu Kevin , Manchanda Gulati Pooja , Johnson Benjamin , Sebastian Ebin , Paixao Becker Aline , Geurts Marjolein , Gray Ashley , Meng Wei , Fleming Jessica , Beyer Sasha , Wang Qi-en , Venere Monica , Jaharul Haque S , Robe Pierre , Chakravarti Arnab 
Published: November 2019

Abstract

BACKGROUND
Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival time of less than 15 months. miRNAs are emerging as promising and novel biomarkers in GBM. The aims of this study are: 1) to investigate novel miRNAs biomarkers that affect tumorigenesis and therapeutic sensitivity, and 2) to study the underlying molecular mechanisms in GBM.

METHODS
Nanostring v3 was performed followed by univariable (UVA) and multivariable (MVA) analyses. Functional studies were conducted to define the role of miR-146a in GBM tumorigenesis and therapeutic response and the molecular mechanisms were investigated.

RESULTS
UVA analyses demonstrated that miR-146a is one of the top miRNAs that correlated with better prognosis in GBM patients (p=9.21E-05), which was independent of MGMT promoter methylation by MVA analyses (p< 0.001). miR-146a expression was significantly downregulated in recurrent GBM tumors compared with the paired primary GBM tumors (p=0.003). Overexpression of miR-146a significantly inhibited tumor cell growth and sensitized patient-derived primary GBM cells to temozolomide (TMZ) treatment in vitro, and showed statistically significant smaller tumor size (p< 0.01) and prolonged survival (p=0.001) in vivo. In addition, miR-146a is downregulated in glioma cancer stem cells, and overexpression of miR-146a significantly affected glioma cancer stem cell self-renewal. We also found that overexpression of miR-146a significantly inhibited the NF-κB, AKT, and ERK pathways.

CONCLUSION
Our data suggest, for the first time, that miR-146a predicts favorable prognosis for GBM patients and sensitizes primary GBM cells to TMZ treatment in vitro and in vivo through regulating glioma stem cells. Importantly, miR-146a may prove to be a master switch shutting off AKT, NF-κB, as well as other pathways and may overcome redundancies among these pathways leading to resistance. FUNDING: Bohnenn Fund (to PR), R01CA108633, R01CA169368, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC).
CMET-10. INTRACRANIAL SOLITARY PITUITARY METASTASIS: THE IMPLICATIONS FROM FIVE CASES
Authors: Shan Changguo , Hong Weiping , Lai Mingyao , Wang Hui , Cai Linbo 
Published: November 2019

Abstract

BACKGROUND
Pituitary gland metastasis is a rare disease which represents only 1% of pituitary gland lesions. Intracranial solitary pituitary metastasis tends to be misdiagnosed as pituitary adenoma, resulting in a delayed anti-tumor treatment.

METHODS
Five cases of patients with pituitary gland metastasis recorded between 2014 and 2018 in our hospital were investigated with reference to patient demographics, symptoms at presentation, radiological and histological findings, management and outcomes.

RESULTS
Five patients (4 male and 1 female) were included and the median age was 48 years (range: 21 to 66). In those five cases, central nervous system related symptoms were the first sign of malignancy, including visual loss (5 in 5 patients), visual field defects (5 in 5 patients), apituitarism (5 in 5 patients), headache (4 in 5 patients), hypothroidism (4 in 5 patients) and diabetes insipidus (2 in 5 patients). All patients received total or partial hypophysectomy and pathologically revealed metastatic adenocarcinoma in 4 patients and metastatic squamous carcinoma in 1 patient. Further examinations by Computed Tomography (CT) or Positron Emission Computed Tomography (PET) indicated lung as primary site in five cases. EGFR mutation and ROS1 fusion were found in 3 and 1 adenocarcinoma patient, respectively, through gene detection of tissue. Postoperative radiotherapy (5 patients), target therapy (4 patients) and chemotherapy (1 patient) were given as subsequent treatment. During the follow-up, four patients died and the overall survival was 2, 8, 28 and 30 months, respectively.

CONCLUSION
We found that pituitary symptoms usually presented as the first sign of malignancy in intracranial solitary pituitary metastasis. Lung is the most frequently primary site, particularly in adenocarcinoma with driver gene mutation. Patients may benefit from multidiscipline treatment, including resection of pituitary metastasis combined with radiotherapy and targeted therapy.