Publications by authors named "Alexandros Bouras"

12 Publications

  • Page 1 of 1

Current knowledge on the immune microenvironment and emerging immunotherapies in diffuse midline glioma.

EBioMedicine 2021 Jul 19;69:103453. Epub 2021 Jun 19.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai,10 Union Square East, 5th Floor, Suite 5E, New York, NY 10003, USA; Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature in critical areas of the brain, the prognosis of DMG remains dismal. DMGs are characterized by unique phenotypic heterogeneity and histological features. Mutations of H3K27M, TP53, and ACVR1 drive DMG tumorigenesis. Histological artifacts include pseudopalisading necrosis and vascular endothelial proliferation. Mouse models that recapitulate human DMG have been used to study key driver mutations and the tumor microenvironment. DMG consists of a largely immunologically cold tumor microenvironment that lacks immune cell infiltration, immunosuppressive factors, and immune surveillance. While tumor-associated macrophages are the most abundant immune cell population, there is reduced T lymphocyte infiltration. Immunotherapies can stimulate the immune system to find, attack, and eliminate cancer cells. However, it is critical to understand the immune microenvironment of DMG before designing immunotherapies since differences in the microenvironment influence treatment efficacy. To this end, our review aims to overview the immune microenvironment of DMG, discuss emerging insights about the immune landscape that drives disease pathophysiology, and present recent findings and new opportunities for therapeutic discovery.
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http://dx.doi.org/10.1016/j.ebiom.2021.103453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220552PMC
July 2021

Akaluc bioluminescence offers superior sensitivity to track in vivo glioma expansion.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa134. Epub 2020 Oct 10.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Longitudinal tracking of tumor growth using noninvasive bioluminescence imaging (BLI) is a key approach for studies of in vivo cancer models, with particular relevance for investigations of malignant gliomas in rodent intracranial transplant paradigms. Akaluciferase (Akaluc) is a new BLI system with higher signal strength than standard firefly luciferase (Fluc). Here, we establish Akaluc BLI as a sensitive method for in vivo tracking of glioma expansion.

Methods: We engineered a lentiviral vector for expression of Akaluc in high-grade glioma cell lines, including patient-derived glioma stem cell (GSC) lines. Akaluc-expressing glioma cells were compared to matching cells expressing Fluc in both in vitro and in vivo BLI assays. We also conducted proof-of-principle BLI studies with intracranial transplant cohorts receiving chemoradiation therapy.

Results: Akaluc-expressing glioma cells produced more than 10 times higher BLI signals than Fluc-expressing counterparts when examined in vitro, and more than 100-fold higher signals when compared to Fluc-expressing counterparts in intracranial transplant models in vivo. The high sensitivity of Akaluc permitted detection of intracranial glioma transplants starting as early as 4 h after implantation and with as little as 5000 transplanted cells. The sensitivity of the system allowed us to follow engraftment and expansion of intracranial transplants of GSC lines. Akaluc was also robust for sensitive detection of in vivo tumor regression after therapy and subsequent relapse.

Conclusion: Akaluc BLI offers superior sensitivity for in vivo tracking of glioma in the intracranial transplant paradigm, facilitating sensitive approaches for the study of glioma growth and response to therapy.
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http://dx.doi.org/10.1093/noajnl/vdaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680182PMC
October 2020

Hyperthermia treatment advances for brain tumors.

Int J Hyperthermia 2020 07;37(2):3-19

Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Hyperthermia therapy (HT) of cancer is a well-known treatment approach. With the advent of new technologies, HT approaches are now important for the treatment of brain tumors. We review current clinical applications of HT in neuro-oncology and ongoing preclinical research aiming to advance HT approaches to clinical practice. Laser interstitial thermal therapy (LITT) is currently the most widely utilized thermal ablation approach in clinical practice mainly for the treatment of recurrent or deep-seated tumors in the brain. Magnetic hyperthermia therapy (MHT), which relies on the use of magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs), is a new quite promising HT treatment approach for brain tumors. Initial MHT clinical studies in combination with fractionated radiation therapy (RT) in patients have been completed in Europe with encouraging results. Another combination treatment with HT that warrants further investigation is immunotherapy. HT approaches for brain tumors will continue to a play an important role in neuro-oncology.
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http://dx.doi.org/10.1080/02656736.2020.1772512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756245PMC
July 2020

Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy's history, efficacy and application in humans.

Int J Hyperthermia 2018 12 6;34(8):1316-1328. Epub 2018 Feb 6.

a Department of Neurosurgery, Brain Tumor Nanotechnology Laboratory , Tisch Cancer Institute at Mount Sinai , New York , NY , USA.

Hyperthermia therapy (HT) is the exposure of a region of the body to elevated temperatures to achieve a therapeutic effect. HT anticancer properties and its potential as a cancer treatment have been studied for decades. Techniques used to achieve a localised hyperthermic effect include radiofrequency, ultrasound, microwave, laser and magnetic nanoparticles (MNPs). The use of MNPs for therapeutic hyperthermia generation is known as magnetic hyperthermia therapy (MHT) and was first attempted as a cancer therapy in 1957. However, despite more recent advancements, MHT has still not become part of the standard of care for cancer treatment. Certain challenges, such as accurate thermometry within the tumour mass and precise tumour heating, preclude its widespread application as a treatment modality for cancer. MHT is especially attractive for the treatment of glioblastoma (GBM), the most common and aggressive primary brain cancer in adults, which has no cure. In this review, the application of MHT as a therapeutic modality for GBM will be discussed. Its therapeutic efficacy, technical details, and major experimental and clinical findings will be reviewed and analysed. Finally, current limitations, areas of improvement, and future directions will be discussed in depth.
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http://dx.doi.org/10.1080/02656736.2018.1430867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078833PMC
December 2018

Convection-enhanced delivery of cetuximab conjugated iron-oxide nanoparticles for treatment of spontaneous canine intracranial gliomas.

J Neurooncol 2018 May 19;137(3):653-663. Epub 2018 Jan 19.

Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.

Cetuximab conjugated iron-oxide nanoparticles (cetuximab-IONPs) have shown both in-vitro and in-vivo anti-tumor efficacy against gliomas. The purpose of this pilot study was to evaluate the safety and potential efficacy of cetuximab-IONPs for treatment of spontaneously occurring intracranial gliomas in canines after convection-enhanced delivery (CED). The use of CED allowed for direct infusion of the cetuximab-IONPs both intratumorally and peritumorally avoiding the blood brain barrier (BBB) and limiting systemic effects. A total of eight dogs participated in the study and only two developed mild post-operative complications, which resolved with medical therapy. All canines underwent a single CED treatment of the cetuximab-IONPs over 3 days and did not receive any further adjuvant treatments. Volumetric analysis showed a median reduction in tumor size of 54.9% by MRI at 1-month (4-6 weeks) follow-up. Five dogs were euthanized due to recurrence of neurological signs other than seizures, two due to recurrent seizures, and one dog died in his sleep. Median survival time after surgery was 248 days (mean 367 days).
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http://dx.doi.org/10.1007/s11060-018-2764-1DOI Listing
May 2018

5-Aminolevulinic Acid Guided Sampling of Glioblastoma Microenvironments Identifies Pro-Survival Signaling at Infiltrative Margins.

Sci Rep 2017 Nov 15;7(1):15593. Epub 2017 Nov 15.

Departments of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, Georgia.

Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5-ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant.
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http://dx.doi.org/10.1038/s41598-017-15849-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688093PMC
November 2017

Selective Interareal Synchronization through Gamma Frequency Differences and Slower-Rhythm Gamma Phase Reset.

Neural Comput 2017 03 20;29(3):643-678. Epub 2016 Oct 20.

Frankfurt Institute for Advanced Studies, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany

The communication-through-coherence (CTC) hypothesis states that a sending group of neurons will have a particularly strong effect on a receiving group if both groups oscillate in a phase-locked ("coherent") manner (Fries, 2005 , 2015 ). Here, we consider a situation with two visual stimuli, one in the focus of attention and the other distracting, resulting in two sites of excitation at an early cortical area that project to a common site in a next area. Taking a modeler's perspective, we confirm the workings of a mechanism that was proposed by Bosman et al. ( 2012 ) in the context of providing experimental evidence for the CTC hypothesis: a slightly higher gamma frequency of the attended sending site compared to the distracting site may cause selective interareal synchronization with the receiving site if combined with a slow-rhythm gamma phase reset. We also demonstrate the relevance of a slightly lower intrinsic frequency of the receiving site for this scenario. Moreover, we discuss conditions for a transition from bottom-up to top-down driven phase locking.
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http://dx.doi.org/10.1162/NECO_a_00908DOI Listing
March 2017

Intraoperative Spectroscopy with Ultrahigh Sensitivity for Image-Guided Surgery of Malignant Brain Tumors.

Anal Chem 2016 Jan 7;88(1):858-67. Epub 2015 Dec 7.

Department of Biomedical Engineering, Emory University and Georgia Institute of Technology , 1760 Haygood Drive, Suite E116, Atlanta, Georgia 30322, United States.

Intraoperative cancer imaging and fluorescence-guided surgery have attracted considerable interest because fluorescence signals can provide real-time guidance to assist a surgeon in differentiating cancerous and normal tissues. Recent advances have led to the clinical use of a natural fluorophore called protoporphyrin IX (PpIX) for image-guided surgical resection of high-grade brain tumors (glioblastomas). However, traditional fluorescence imaging methods have only limited detection sensitivity and identification accuracy and are unable to detect low-grade or diffuse infiltrating gliomas (DIGs). Here we report a low-cost hand-held spectroscopic device that is capable of ultrasensitive detection of protoporphyrin IX fluorescence in vivo, together with intraoperative spectroscopic data obtained from both animal xenografts and human brain tumor specimens. The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. For detection specificity, intraoperative spectroscopy allows the differentiation of brain tumor cells from normal brain cells with a contrast signal ratio over 100. In vivo animal studies reveal that protoporphyrin IX fluorescence is strongly correlated with both MRI and histological staining, confirming that the fluorescence signals are highly specific to tumor cells. Furthermore, ex vivo spectroscopic studies of excised brain tissues demonstrate that the hand-held spectroscopic device is capable of detecting diffuse tumor margins with low fluorescence contrast that are not detectable with current systems in the operating room. These results open new opportunities for intraoperative detection and fluorescence-guided resection of microscopic and low-grade glioma brain tumors with invasive or diffusive margins.
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http://dx.doi.org/10.1021/acs.analchem.5b03453DOI Listing
January 2016

Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles.

J Neurooncol 2015 Aug 17;124(1):13-22. Epub 2015 May 17.

Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.

The epidermal growth factor receptor deletion variant EGFRvIII is known to be expressed in a subset of patients with glioblastoma (GBM) tumors that enhances tumorigenicity and also accounts for radiation and chemotherapy resistance. Targeting the EGFRvIII deletion mutant may lead to improved GBM therapy and better patient prognosis. Multifunctional magnetic nanoparticles serve as a potential clinical tool that can provide cancer cell targeted drug delivery, imaging, and therapy. Our previous studies have shown that an EGFRvIII-specific antibody and cetuximab (an EGFR- and EGFRvIII-specific antibody), when bioconjugated to IONPs (EGFRvIII-IONPs or cetuximab-IONPs respectively), can simultaneously provide sensitive cancer cell detection by magnetic resonance imaging (MRI) and targeted therapy of experimental GBM. In this study, we investigated whether cetuximab-IONPs can additionally allow for the radiosensitivity enhancement of GBM. Cetuximab-IONPs were used in combination with single (10 Gy × 1) or multiple fractions (10 Gy × 2) of ionizing radiation (IR) for radiosensitization of EGFRvIII-overexpressing human GBM cells in vitro and in vivo after convection-enhanced delivery (CED). A significant GBM antitumor effect was observed in vitro after treatment with cetuximab-IONPs and subsequent single or fractionated IR. A significant increase in overall survival of nude mice implanted with human GBM xenografts was found after treatment by cetuximab-IONP CED and subsequent fractionated IR. Increased DNA double strands breaks (DSBs), as well as increased reactive oxygen species (ROS) formation, were felt to represent the mediators of the observed radiosensitization effect with the combination therapy of IR and cetuximab-IONPs treatment.
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http://dx.doi.org/10.1007/s11060-015-1807-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498963PMC
August 2015

Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles.

Oncotarget 2015 Apr;6(11):8788-806

Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.

Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496184PMC
http://dx.doi.org/10.18632/oncotarget.3554DOI Listing
April 2015

Nanotechnology applications for glioblastoma.

Neurosurg Clin N Am 2012 Jul 14;23(3):439-49. Epub 2012 Jun 14.

Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.

Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. Although conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds promise in the use of multifunctional nanoparticles for imaging and targeted therapy of glioblastoma. This article examines the current state of nanotechnology in the treatment of glioblastoma and directions of further study.
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http://dx.doi.org/10.1016/j.nec.2012.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473084PMC
July 2012

Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy.

Expert Rev Clin Pharmacol 2012 Mar;5(2):173-86

Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, 1365B Clifton Road NE, Suite 6200, Atlanta, GA 30322, USA.

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood-brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.
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http://dx.doi.org/10.1586/ecp.12.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461264PMC
March 2012
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