scholarly journals PS2 - 178 Brevican-Specific Peptides for the Development of Next-Generation Targeted Theranostics for High Grade Gliomas

2016 ◽  
Vol 43 (S4) ◽  
pp. S14-S14
Author(s):  
C.F. Cho ◽  
K. Kasai ◽  
J. Wolfe ◽  
K. Hornburg ◽  
F. Bononi ◽  
...  
Keyword(s):  
Magnetic Particles ◽  
Glioma Cells ◽  
Specific Protein ◽  
Cell Uptake ◽  
Detection Methods ◽  
High Grade ◽  
Current Standard ◽  
Anti Cancer ◽  
High Grade Gliomas ◽  
Theranostic Agents

High-grade gliomas are deadly cancers, and current standard-of-care has demonstrated limited success. The ability to specifically target glioma cells can allow for the development of improved theranostic agents leading to better detection methods, as well as safer anti-cancer therapies. Brevican (Bcan), a CNS-specific protein is upregulated in glioma cells and correlates with tumor progression. Particularly, a Bcan isoform lacking normal glycosylation, called B/bDg is a unique glioma marker and is not expressed in non-cancerous tissues. Therefore, B/bDg represents a valuable target for anti-cancer strategies. We describe here the discovery of novel high-affinity B/bDg-targeted peptides using rapid combinatorial library screening approaches and a microfluidic sorting device of our own design. Briefly, a one-bead-one-compound (OBOC) peptide library was screened against small magnetic particles decorated with B/bDg. Positive “hit” beads labeled with magnetic particles were isolated using an inexpensive but yet, accurate and high-throughput in-house microfluidic magnetic-activated sorter. These hits were exposed to cells expressing B/bDg, and beads with the highest cell association were isolated and sequenced. Seven novel peptides were identified. Cell uptake analyses and blocking studies revealed that 5 of these peptides displayed specific uptake in B/bDg-overexpressing cells. These candidates displayed nano-/micromolar binding affinity for recombinant B/bDg protein. Further analyses of these candidates using confocal microscopy revealed increased peptide binding/uptake in patient-derived glioma stem cells (GSCs) compared with primary human astrocytes. We plan to incorporate these onto multi-functional BBB-penetrating nanoparticles loaded with imaging agents or a drug payload to translate them into highly selective and efficacious brain cancer theranostic agents.

scholarly journals Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence

2019 ◽  
Vol 20 (1) ◽  
pp. 331-357 ◽  
Author(s):  
Michael W. Graner
Keyword(s):  
Extracellular Vesicles ◽  
Standard Of Care ◽  
High Grade ◽  
Biological Processes ◽  
Current Standard ◽  
Endocrine Factors ◽  
High Grade Gliomas ◽  
Endosomal System ◽  
Intercellular Communications

High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ. One area of rejuvenated study relates to extracellular vesicles (EVs)—membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood–brain barrier, and the ensuing inflammation), and influences on the immune system (both stimulatory and suppressive). This article reviews glioma EVs and the ways that EVs manifest themselves as autocrine, paracrine, and endocrine factors in proximal and distal intra- and intercellular communications. The reader should note that there is much controversy, and indeed confusion, in the field over the exact roles for EVs in many biological processes, and we will engage some of these difficulties herein.

Is Current Technology Improving Outcomes with Radiation Therapy for Gliomas?

2014 ◽  
pp. e89-e94 ◽  
Author(s):  
Michael Brada ◽  
Brian Haylock
Keyword(s):  
Normal Tissue ◽  
Three Dimensional ◽  
Principal Component ◽  
High Grade ◽  
Current Standard ◽  
Heavy Charged Particles ◽  
Novel Technologies ◽  
Altered Fractionation ◽  
Specialized Equipment ◽  
High Grade Gliomas

Radiotherapy (RT) remains the principal component of glioma treatment, and three-dimensional conformal RT (3DCRT) is the current standard of RT delivery. Advances in imaging and in RT technology have enabled more precise treatment to defined targets combined with better means of avoiding critical normal structures, and this is complemented by intensive quality assurance, which includes on-treatment imaging. The refinements of 3DCRT include intensity modulated RT (IMRT), arcing IMRT, and high-precision conformal RT, formerly described as “stereotactic,” which can be delivered using a linear accelerator or other specialized equipment. Although proton therapy uses heavy charged particles, the principal application can also be considered as refinement of 3DCRT. The technologies generally improve the dose differential between the tumor and normal tissue and enable more dose-intensive treatments. However, these have not translated into improved survival outcome in patients with low- and high-grade gliomas. More intensive altered fractionation regimens have also failed to show survival benefit. Nevertheless, novel technologies enable better sparing of normal tissue and selective avoidance of critical structures, and these need to be explored further to improve the quality of life of patients with gliomas. Principal clinical advance in RT has been the recognition that less intensive treatments are beneficial for patients with adverse prognosis high-grade gliomas. We conclude that the principal gain of modern RT technology is more likely to emerge as a reduction in treatment related toxicity rather than as an improvement in overall survival; the optimal avoidance strategies remain to be defined.

scholarly journals Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance

2015 ◽  
Vol 122 (6) ◽  
pp. 1360-1369 ◽  
Author(s):  
Roberto Jose Diaz ◽  
Roberto Rey Dios ◽  
Eyas M. Hattab ◽  
Kelly Burrell ◽  
Patricia Rakopoulos ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Low Dose ◽  
Glioma Cells ◽  
High Grade ◽  
Fluorescein Sodium ◽  
Tumor Margins ◽  
Histopathological Correlation ◽  
High Grade Gliomas

OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.

TAMI-28. IDENTIFICATION OF A NEUROLIGIN-3 BINDING PARTNER IN HIGH-GRADE GLIOMAS AND NORMAL PROGENITORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Shawn Gillespie ◽  
Yoon Seok Kim ◽  
Anna Geraghty ◽  
Michael Quezada ◽  
James Reed ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Glioma Cells ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Size Exclusion ◽  
Dependent Manner ◽  
High Grade ◽  
Gamma Secretase ◽  
Binding Partner ◽  
High Grade Gliomas

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma, are lethal cancers whose progression is strongly regulated by neuronal activity. One way in which gliomas detect neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is shed from neurons and oligodendrocyte precursors (OPCs) by the ADAM10 sheddase in an activity dependent manner. NLGN3 signaling drives glioma growth, but the cognate binding partner of shed NLGN3 (sNLGN3) on glioma cells is unknown. Here, we employed a proximity labeling technique to identify chondroitin sulfate proteoglycan 4 (CSPG4) as a putative binding partner of sNLGN3 in gliomas. We then confirmed complexing between recombinant proteins with size exclusion chromatography and are determining kinetics and affinity by surface plasmon resonance. When looking for evidence of binding in cells, we were surprised to find that sNLGN3 triggers regulated intramembrane proteolysis (RIP) of CSPG4, leaving no trace of the interaction at the membrane. sNLGN3 binding first induces ADAM10-mediated cleavage and release of the CSPG4 ectodomain, followed by gamma secretase-mediated release of the intracellular domain and downstream signaling in OPCs and gliomas. Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks sNLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of sNLGN3 in vitro. Furthermore, we find that tamoxifen-induced deletion of NLGN3 from murine OPCs reduces the total number of OPCs, suggesting that this signaling axis promotes maintenance of OPC stemness in an autocrine fashion. Indeed, gamma secretase inhibition accelerates OPC differentiation in vitro, pointing towards a fundamental role for sNLGN3-CSPG4 signaling in OPCs and high-grade gliomas. Altogether, our results form a critical missing link in understanding how glioma cells detect a key neuronal activity-regulated signal, suggest intriguing links to OPC biology and identify a therapeutic target to disrupt neuron-glioma interactions.

TAMI-47. MIR-542-3P CONTRIBUTES TO THE HK2-MEDIATED HIGH GLYCOLYTIC PHENOTYPE IN HUMAN GLIOMA CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi208-vi208
Author(s):  
Junhyung Kim ◽  
Min Woo Park ◽  
Ju Won Ahn ◽  
Jeong Min Sim ◽  
Suwan Kim ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cellular Proliferation ◽  
Glioma Cells ◽  
Low Grade ◽  
High Grade ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Glycolytic Activity ◽  
High Grade Gliomas ◽  
Glycolytic Phenotype

Abstract BACKGROUND The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear. METHODS We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis. RESULTS We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database. CONCLUSIONS miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.

Current strategies for the treatment of malignant gliomas – experience of the Department of Neurosurgery, Brodno Masovian Hospital in Warsaw

2020 ◽  
Vol 92 (4) ◽  
pp. 1-5
Author(s):  
Grzegorz Turek ◽  
Tomasz Pasterski ◽  
Krzysztof Bankiewicz ◽  
Sebastian Dzierzęcki ◽  
Mirosław Ząbek
Keyword(s):  
Brain Tumors ◽  
San Francisco ◽  
Malignant Gliomas ◽  
High Grade ◽  
Current Standard ◽  
Convection Enhanced Delivery ◽  
Surgical Methods ◽  
High Grade Gliomas ◽  
Standard Medical Treatment ◽  
Intraoperative Electrical Stimulation

Introduction: Malignant gliomas (HGG) are the most common primary malignant brain tumors arising from glial cells. Between HGG, glioblastoma is the most common and the most malignant histological subtype with only a 27% 2-year survival rate. Current standard medical treatment of malignant gliomas is still not satisfactory, and may need some development and modification. We presented and discussed the achievements of the Department of Neurosurgery at Brodno Masovian Hospital in the treatment of malignant gliomas. Material and methods: We step by step presented and discussed the policy in the treatment of malignant gliomas. We showed all steps starting from preparation of surgery (eg. neuroimaging) and finishing on the presentation the development of perioperative management – from intraoperative electrical stimulation mapping and monitoring which is nowadays already standard method to convection-enhanced delivery (CED) and gamma knife (GK) which are new and promising methods in the treatment of glioblastoma. Results: All surgical methods described in this manuscript were introduced to achieve maximal and safe resection of malignant glioma. CED and GK are the last resort methods for patients with recurrent HGG. Discussion: Department of Neurosurgery at Brodno Masovian Hospital deal with all types of brain tumors, including all types of high grade gliomas. As the first Department in Europe with close cooperation with the Department of Neurosurgery in San Francisco, we have started local infusions of drugs directly to the tumor in the real time of magnetic field, and we think that technology may change all approaches to the treatment of high grade gliomas.

scholarly journals Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives

2021 ◽  
Vol 10 (7) ◽  
pp. 1367
Author(s):  
Pasquale Persico ◽  
Elena Lorenzi ◽  
Angelo Dipasquale ◽  
Federico Pessina ◽  
Pierina Navarria ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
High Grade ◽  
Current Standard ◽  
Advanced Malignancies ◽  
The Status ◽  
High Grade Gliomas

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.

scholarly journals HGG-21. MALIGNANT SYNAPTIC PLASTICITY IN PEDIATRIC HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i21-i21
Author(s):  
Kathryn Taylor ◽  
Tara Barron ◽  
Griffin Hartmann ◽  
Helena Zhang ◽  
Alexa Hui ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Glioma Cells ◽  
Membrane Properties ◽  
High Grade ◽  
Synaptic Regulation ◽  
Electrophysiological Recordings ◽  
Glioma Xenograft ◽  
Synaptic Neurotransmission ◽  
High Grade Gliomas ◽  
Cell Depolarization

Abstract Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicate the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

Effect of metformin and statins in high-grade brain tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2091-2091
Author(s):  
Guek Eng Lee ◽  
Iain B. Tan ◽  
Chee Kian Tham
Keyword(s):  
Diabetes Mellitus ◽  
Overall Survival ◽  
Confidence Interval ◽  
Median Survival ◽  
Brain Tumours ◽  
High Dose ◽  
Average Dose ◽  
High Grade ◽  
Anti Cancer ◽  
High Grade Gliomas

2091 Background: Metformin and statins are thought to have anti-cancer properties. Metformin induces AMPK activation and may be implicated in potentiating the therapeutic outcome of temazolamide. Statins at low dose are thought to have anti-cancer properties by inhibiting pro-angiogenic factors with resultant inhibition of tumor growth, but statins at high dose are thought to have counter-productive effects. Hyperglycaemia was shown to be associated with a poorer outcome in patients with newly diagnosed glioblastoma. Hence we investigate the effect of metformin and statins in high grade brain tumours. Methods: Among 249 patients with brain tumour, we identified 142 patients with high grade gliomas. 116 patients did not receive metformin or statins and 26 patients received metformin or statins. Patients’ demographics, clinical and histopathological characteristics were recorded. Overall survival was evaluated. Results: Among 142 patients with high grade gliomas, there were 86 patients with glioblastoma multiforme, and 56 patients with anaplastic astrocytoma or anaplastic oligodendroma. Median age was 60 years old. The average value of HbA1c value for patients on metformin was 7.2%. The average dose of simvastatin used was 20 mg and average total cholesterol was 5.1mmol/l. For patients who did not receive metformin or statins, the median survival was 72.9 months (95% confidence interval, 47.8 – 98.1); patients who received metformin or statins, the median survival was 39.1 months (95% confidence interval, 21.7 – 56.4) p = 0.24. Conclusions: There is a trend towards shorter overall survival of patients who received metformin and statins. Despite the anti-cancer properties of metformin and statins, patients with diabetes mellitus and hyperlipidaemia still fare worse. The effect of diabetes mellitus, hyperlipidaemia, as well as sugar and cholesterol control deserves a larger cohort study in patients with high grade brain tumours.

Sign in / Sign up

Export Citation Format

Share Document