scholarly journals Receptor-Targeted Glial Brain Tumor Therapies

2018 ◽  
Vol 19 (11) ◽  
pp. 3326 ◽  
Author(s):  
Puja Sharma ◽  
Waldemar Debinski
Keyword(s):  
Brain Tumors ◽  
Malignant Gliomas ◽  
Unmet Need ◽  
Normal Brain ◽  
Therapeutic Approaches ◽  
Multiple Tumor ◽  
Multiple Receptors ◽  
Clinical Responses ◽  
Drug Activation ◽  
Targeted Therapeutic

Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

scholarly journals Diffusion Histology Imaging Differentiates Distinct Pediatric Brain Tumor Histology

2020 ◽  
Author(s):  
Zezhong Ye ◽  
Komal Sriniv ◽  
Ashely Meyer ◽  
Peng Sun ◽  
Joshua Lin ◽  
...  
Keyword(s):  
Neural Network ◽  
Brain Tumors ◽  
Deep Neural Network ◽  
Unmet Need ◽  
Pediatric Brain Tumor ◽  
High Grade ◽  
Pediatric Tumor ◽  
Multiple Tumor ◽  
Tumor Histology ◽  
Pediatric Brain

Abstract Background: High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. Methods: We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. Results: DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 83.3%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95%CI) of 0.983 (0.985 - 0.989), 0.961 (0.957 - 0.964), 0.993 (0.992 - 0.994), 0.953 (0.947 - 0.958), 0.974 (0.970 - 0.978) and 0.980 (0.977 - 0.983) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Conclusions: Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.

scholarly journals Diffusion histology imaging differentiates distinct pediatric brain tumor histology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zezhong Ye ◽  
Komal Srinivasa ◽  
Ashely Meyer ◽  
Peng Sun ◽  
Joshua Lin ◽  
...  
Keyword(s):  
Neural Network ◽  
Brain Tumors ◽  
Deep Neural Network ◽  
Unmet Need ◽  
Pediatric Brain Tumor ◽  
High Grade ◽  
Pediatric Tumor ◽  
Multiple Tumor ◽  
Tumor Histology ◽  
Pediatric Brain

AbstractHigh-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982–0.986), 0.960 (0.956–0.963), 0.991 (0.990–0.993), 0.950 (0.944–0.956), 0.977 (0.973–0.981) and 0.976 (0.972–0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.

Metabolic profiles of ketolysis and glycolysis in malignant gliomas: Possible predictors of response to ketogenic diet therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13048-e13048
Author(s):  
Howard T. Chang ◽  
Lawrence Karl Olson ◽  
Kenneth A. Schwartz
Keyword(s):  
Brain Tumors ◽  
Ketogenic Diet ◽  
Malignant Gliomas ◽  
Diet Therapy ◽  
Normal Brain ◽  
Mitochondrial Enzymes ◽  
Model Studies ◽  
Predictors Of Response ◽  
Coa Transferase ◽  
Formalin Fixed Paraffin Embedded

e13048 Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human brain tumors may also be sensitive to ERKD, we used immunohistochemistry reactions on formalin fixed paraffin embedded tumor samples to evaluate for the presence of enzymes important for the metabolism of ketones and glucose. Methods: Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: low positive<5% (LOW); intermediate (INT) 5-20%; and highly positive (HIGH) >20%. Focal non-neoplastic “normal” brain tissue present within the specimens served as positive internal controls. Results: Succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) are mitochondrial enzymes important for metabolizing beta hydroxy butyrate, the main ketone in blood. Both of these enzymes were either decreased or absent (INT or LOW) concordantly in 14 of the 17 (82%) GBMs, and in 1 of 6 (17%) anaplastic astrocytomas (AA). Two of the enzymes in the glycolytic pathway hexokinase-2 and pyruvate kinase M2 were concordantly LOW or INT in only 3 of the 17 GBMs that also were LOW or INT for both OXCT1 and BDH1. The remaining brain tumors were positive for at least one of these glycolytic enzymes. Mitochondrial enzymes were not globally deficient. The mitochondrial enzyme acetyl CoA transferase (ACAT1) was present in 9 of the 14 GBM specimens that were LOW or INT for the mitochondrial enzymes OXCT1 and BDH1. Conclusions: Our data showing that many, but not all, malignant gliomas lack ketolytic enzymes, support the rationale of ERKD as investigational treatment for patients with malignant gliomas. Moreover, we hypothesize that it is important to test individual tumor samples for the expression of these enzymes prior to ERKD, as patients with malignant gliomas that have diminished capacity to metabolize ketones likely may derive the most benefit from ERKD.

scholarly journals Bioreactors for Decreasing the Growth of Brain Tumors

2001 ◽  
Vol 1 ◽  
pp. 194-195
Author(s):  
Rona S. Carroll ◽  
Marcelle Machluf
Keyword(s):  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Median Survival Time ◽  
Malignant Gliomas ◽  
Normal Brain ◽  
Malignant Phenotype ◽  
Dividing Cells ◽  
Aggressive Tumors ◽  
High Degree ◽  
Neurosurgical Techniques

Malignant gliomas are the most common primary brain tumors. They are highly aggressive tumors characterized by a recurrence rate of virtually 100%. Despite significant advances in neuroimaging and neurosurgical techniques, the median survival time of patients with glioblastoma multiforme remains 12 to 18 months. Malignant gliomas are characterized by rapidly dividing cells, which invade into the normal brain, and a high degree of vascularity. Recent experimental evidence indicates that tumor-related angiogenesis contributes significantly to the malignant phenotype.

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals IMMU-45. CUSTOMIZED LIPID NANOPARTICLES DELIVER NUCLEIC ACIDS TO IMMUNE CELLS IN BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii114-ii114
Author(s):  
Adam Grippin ◽  
Brandon Wummer ◽  
Hector Mendez-Gomez ◽  
Tyler Wildes ◽  
Kyle Dyson ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Nucleic Acids ◽  
Immune Cells ◽  
White Blood Cells ◽  
Lipid Nanoparticles ◽  
Intracranial Tumor ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Normal Brain ◽  
Innate Immune Cells

Abstract BACKGROUND Brain tumors are notoriously difficult to treat in part due to their isolation behind the blood brain barrier and their power to suppress antitumor immune responses. We have previously reported cationic liposome formulations capable of delivering immune modulatory nucleic acids to immune cells in various peripheral organs, but there is currently no reliable method to deliver nucleic acids into brain tumors without direct injection into the tumor site. OBJECTIVE Here, we report the development of a customized lipid nanoparticle to deliver immune modulatory nucleic acids to immune cells in brain tumors. APPROACH Cationic liposomes composed of varying lipid combinations were evaluated for their ability to deliver functional mRNA and siRNA to innate immune cells in vitro and in intracranial tumor models. Nucleic acids were labelled with Cy3 to monitor particle distribution in vivo. RESULTS Lipids composed of DOTAP and cholesterol selectively delivered mRNA and siRNA to intracranial GL261 and KR158b tumors. Interestingly, these particles selectively delivered these nucleic acids to CD45+ white blood cells with minimal delivery to CD45- tumor cells or normal brain tissue. Encapsulation of siRNA blocking programmed death ligand 1 (PDL1) significantly reduced PDL1 expression on innate immune cells in brain tumors, with the greatest effects on tumor-associated macrophages. Co-administration of systemic checkpoint blockade with intravenous administration of these lipid nanoparticles bearing PDL1 siRNA enabled systemic and intratumoral checkpoint blockade, leading to 37% long term survivorship in an otherwise fatal intracranial tumor model. CONCLUSIONS Our customized lipid nanoparticles enable potent intratumoral immune modulation via delivery of nucleic acids to immune cells in brain tumors.

scholarly journals Elucidating distinct clinico-radiologic signatures in the borderland between neuromyelitis optica and multiple sclerosis

2021 ◽  
Author(s):  
Maciej Juryńczyk ◽  
Elżbieta Klimiec-Moskal ◽  
Yazhuo Kong ◽  
Samuel Hurley ◽  
Silvia Messina ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Unmet Need ◽  
Transverse Myelitis ◽  
Overlap Syndrome ◽  
Brain Lesions ◽  
Central Vein ◽  
Normal Brain ◽  
Group 4 ◽  
Group 2

Abstract Background Separating antibody-negative neuromyelitis optica spectrum disorders (NMOSD) from multiple sclerosis (MS) in borderline cases is extremely challenging due to lack of biomarkers. Elucidating different pathologies within the likely heterogenous antibody-negative NMOSD/MS overlap syndrome is, therefore, a major unmet need which would help avoid disability from inappropriate treatment. Objective In this study we aimed to identify distinct subgroups within the antibody-negative NMOSD/MS overlap syndrome. Methods Twenty-five relapsing antibody-negative patients with NMOSD features underwent a prospective brain and spinal cord MRI. Subgroups were identified by an unsupervised algorithm based on pre-selected NMOSD/MS discriminators. Results Four subgroups were identified. Patients from Group 1 termed “MS-like” (n = 6) often had central vein sign and cortical lesions (83% and 67%, respectively). All patients from Group 2 (“spinal MS-like”, 8) had short-segment myelitis and no MS-like brain lesions. Group 3 (“classic NMO-like”, 6) had high percentage of bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM, 80% and 60%, respectively) and normal brain appearance (100%). Group 4 (“NMO-like with brain involvement”, 5) typically had a history of NMOSD-like brain lesions and LETM. When compared with other groups, Group 4 had significantly decreased fractional anisotropy in non-lesioned tracts (0.46 vs. 0.49, p = 0.003) and decreased thalamus volume (0.84 vs. 0.98, p = 0.04). Conclusions NMOSD/MS cohort contains distinct subgroups likely corresponding to different pathologies and requiring tailored treatment. We propose that non-conventional MRI might help optimise diagnosis in these challenging patients.

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