Life Sciences Commons^™

Advancements In Dendritic Cell Vaccination: Enhancing Efficacy And Optimizing Combinatorial Strategies For The Treatment Of Glioblastoma, Robert Subtirelu, Eric Teichner, Arjun Ashok, Chitra Parikh, Sahithi Talasila, Irina-Mihaela Matache, Ahab Alnemri, Victoria Anderson, Osmaan Shahid, Sricharvi Mannam, Andrew Lee, Thomas Werner, Mona-Elisabeth Revheim, Abass Alavi

Student Papers, Posters & Projects

Glioblastomas (GBM) are highly invasive, malignant primary brain tumors. The overall prognosis is poor, and management of GBMs remains a formidable challenge, necessitating novel therapeutic strategies such as dendritic cell vaccinations (DCVs). While many early clinical trials demonstrate an induction of an antitumoral immune response, outcomes are mixed and dependent on numerous factors that vary between trials. Optimization of DCVs is essential; the selection of GBM-specific antigens and the utilization of ¹⁸F-fludeoxyglucose Positron Emission Tomography (FDG-PET) may add significant value and ultimately improve outcomes for patients undergoing treatment for glioblastoma. This review provides an overview of the mechanism of …

Spatiotemporally Dynamic Electric Fields For Brain Cancer Treatment: An In Vitro Investigation, Erin Iredale, Abdulla Elsaleh, Hu Xu, Paul Christiaans, Andrew Deweyert, John Ronald, Susanne Schmid, Matthew O Hebb, Terry M Peters, Eugene Wong

Anatomy and Cell Biology Publications

Objective. The treatment of glioblastoma (GBM) using low intensity electric fields (∼1 V cm^-1) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device for in vitro experiments, and evaluated the human GBM cellular responses to these fields. Approach. After measuring the electrical conductivity of the in vitro culturing medium, we designed experiments to evaluate the …

Natural Coevolution Of Tumor And Immunoenvironment In Glioblastoma., Lingxiang Wu, Wei Wu, Junxia Zhang, Zheng Zhao, Liangyu Li, Mengyan Zhu, Min Wu, Fan Wu, Fengqi Zhou, Yuxin Du, Rui-Chao Chai, Wei Zhang, Xiaoguang Qiu, Quanzhong Liu, Ziyu Wang, Jie Li, Kening Li, Apeng Chen, Yinan Jiang, Xiangwei Xiao, Han Zou, Rashmi Srivastava, Tingting Zhang, Yun Cai, Yuan Liang, Bin Huang, Ruohan Zhang, Fan Lin, Lang Hu, Xiuxing Wang, Xu Qian, Sali Lv, Baoli Hu, Siyuan Zheng, Zhibin Hu, Hongbing Shen, Yongping You, Roel G W Verhaak, Tao Jiang, Qianghu Wang

Faculty Research 2022

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A-FOSL2 axis. High-NES tumor cells could recruit and polarize …

Planning System For The Optimization Of Electric Field Delivery Using Implanted Electrodes For Brain Tumor Control, Erin Iredale, Brynn Voigt, Adam Rankin, Kyungho W Kim, Jeff Z Chen, Susanne Schmid, Matthew O Hebb, Terry M Peters, Eugene Wong

Anatomy and Cell Biology Publications

BACKGROUND: The use of non-ionizing electric fields from low-intensity voltage sources (< 10 V) to control malignant tumor growth is showing increasing potential as a cancer treatment modality. A method of applying these low-intensity electric fields using multiple implanted electrodes within or adjacent to tumor volumes has been termed as intratumoral modulation therapy (IMT).

PURPOSE: This study explores advancements in the previously established IMT optimization algorithm, and the development of a custom treatment planning system for patient-specific IMT. The practicality of the treatment planning system is demonstrated by implementing the full optimization pipeline on a brain phantom with robotic electrode implantation, postoperative imaging, and treatment stimulation.

METHODS: The integrated planning pipeline in 3D Slicer begins with importing and segmenting patient magnetic resonance images (MRI) or computed tomography (CT) images. The segmentation process is manual, followed by a semi-automatic smoothing step that allows …

Cdc20 Regulates Sensitivity To Chemotherapy And Radiation In Glioblastoma Stem Cells., Diane D Mao, Ryan T Cleary, Amit D Gujar, Tatenda Mahlokozera, Albert H Kim

Faculty Research 2022

Glioblastoma stem cells (GSCs) are an important subpopulation in glioblastoma, implicated in tumor growth, tumor recurrence, and radiation resistance. Understanding the cellular mechanisms for chemo- and radiation resistance could lead to the development of new therapeutic strategies. Here, we demonstrate that CDC20 promotes resistance to chemotherapy and radiation therapy. CDC20 knockdown does not increase TMZ- and radiation-induced DNA damage, or alter DNA damage repair, but rather promotes cell death through accumulation of the pro-apoptotic protein, Bim. Our results identify a CDC20 signaling pathway that regulates chemo- and radiosensitivity in GSCs, with the potential for CDC20-targeted therapeutic strategies in the treatment …

Central Nervous System Immune Interactome Is A Function Of Cancer Lineage, Tumor Microenvironment, And Stat3 Expression., Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel G W Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Ben A Freiberg, Charles David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger

Faculty Research 2022

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ …

Plasma Induced Reactive Oxygen Species-Dependent Cytotoxicity In Glioblastoma 3d Tumourspheres, Janith Wanigasekara, Carlos Barcia, Patrick J. Cullen, Brijesh Tiwari, James F. Curtin

Articles

The aim of this study was to determine the effects of a pin‐to‐plate cold atmospheric plasma (CAP) on U‐251 MG three‐dimensional (3D) glioblastoma spheroids under different conditions. 3D tumorspheres showed higher resistance to the CAP treatment compared to 2D monolayer cells. A single CAP treatment was able to induce cytotoxicity, while multiple CAP treatments augmented this effect. CAP was also able to induce cytotoxicity throughout the tumoursphere, and we identified that reactive oxygen species(ROS) plays a major role, while H2O2plays a partial role in CAP‐induced cytotoxicity in tumour-spheres. We conclude that ROS‐dependent cytotoxicity is induced uniformly throughout glioblastoma and epidermoid …

The Synthesis And Biological Assessment Of Novel Ursolic Acid Derivatives As Potential Chemotherapeutic Agents For Cancer, Julie Rose Mae Mondala

Theses

Glioblastoma (GBM) is considered to be the most biologically aggressive type of brain tumour accounting for approximately 48% of all malignant primary brain tumours. GBM patients diagnosed have poor prognosis with a low five-year survival rate of

The aim of this study was to develop novel UA derivatives to enhance its bioavailability. Nine novel UA derivatives: three different diamine linkers, with Boc-protected and deprotected ends, and with folic acid were designed and synthesized to improve compound activity and/or delivery. The structures of the newly synthesised compounds were confirmed using mass spectrometry, FTIR, 1H NMR and 13C NMR. The structural activity …

Homozygous Mtap Deletion In Primary Human Glioblastoma Is Not Associated With Elevation Of Methylthioadenosine., Yasaman Barekatain, Jeffrey J Ackroyd, Victoria C Yan, Sunada Khadka, Lin Wang, Ko-Chien Chen, Anton H Poral, Theresa Tran, Dimitra K Georgiou, Kenisha Arthur, Yu-Hsi Lin, Nikunj Satani, Elliot S Ballato, Eliot I Behr, Ana C Decarvalho, Roel G W Verhaak, John De Groot, Jason T Huse, John M Asara, Raghu Kalluri, Florian L Muller

Faculty Research 2021

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate …

Inhibition Of Hdac1/2 Along With Trap1 Causes Synthetic Lethality In Glioblastoma Model Systems, Trang T. T. Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin

Publications and Research

The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and …

Metabolic Reprogramming By C-Met Inhibition As A Targetable Vulnerability In Glioblastoma, Trang Thi Thu Nguyen, Enyuan Shang, Georg Karpel-Massler, Markus D. Siegelin

Publications and Research

The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in …

Machine Learning Prediction Of Glioblastoma Patient One-Year Survival, Andrew Du '20, Warren Mcgee, Jane Y. Wu

Student Publications & Research

Glioblastoma (GBM) is a grade IV astrocytoma formed primarily from cancerous astrocytes and sustained by intense angiogenesis. GBM often causes non-specific symptoms, creating difficulty for diagnosis. This study aimed to utilize machine learning techniques to provide an accurate one-year survival prognosis for GBM patients using clinical and genomic data from the Chinese Glioma Genome Atlas. Logistic regression (LR), support vector machines (SVM), random forest (RF), and ensemble models were used to identify and select predictors for GBM survival and to classify patients into those with an overall survival (OS) of less than one year and one year or greater. With …

Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin

Publications and Research

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-¹³C-glucose and U-¹³C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading …

Topoisomerase And Tyrosyl-Dna-Phosphodiesterase Ratio As An Indicator For The Response Of Glioblastoma Cancer To Topoisomerase Targeting Anticancer Drugs, Wenjie Wang

FIU Electronic Theses and Dissertations

Glioblastoma (GBM) patients have an estimated survival of ~15 months, with the standard of care (surgery, radiation, and chemotherapy) that has only modestly enhanced patient survival. Identifying biomarkers representing vulnerabilities in GBM biology may allow for the selection of effective and safe chemotherapy options. Irinotecan (IRT), a genotoxic compound currently in clinical trials for GBM, targets topoisomerase I (TOP1) by forming an irreversible ternary DNA-TOP1 cleavage complex (TOP1cc) and leads to apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that rescues TOP1cc and reduces the effectiveness of IRT. In the current study, we evaluate the value of the …

Buparlisib In Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase Ii Trial., Patrick Y Wen, Mehdi Touat, Brian M Alexander, Ingo K Mellinghoff, Shakti Ramkissoon, Christine S Mccluskey, Kristine Pelton, Sam Haidar, Sankha S Basu, Sarah C Gaffey, Loreal E Brown, Juan Emmanuel Martinez-Ledesma, Shaofang Wu, Jungwoo Kim, Wei Wei, Mi-Ae Park, Jason T Huse, John G Kuhn, Mikael L Rinne, Howard Colman, Nathalie Y R Agar, Antonio M Omuro, Lisa M Deangelis, Mark R Gilbert, John F De Groot, Timothy F Cloughesy, Andrew S Chi, Thomas M Roberts, Jean J Zhao, Eudocia Q Lee, Lakshmi Nayak, James R Heath, Laura L Horky, Tracy T Batchelor, Rameen Beroukhim, Susan M Chang, Azra H Ligon, Ian F Dunn, Dimpy Koul, Geoffrey S Young, Michael D Prados, David A Reardon, W K Alfred Yung, Keith L Ligon

Articles, Abstracts, and Reports

PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once …

Diffuse Intrinsic Pontine Glioma Cells Are Vulnerable To Low Intensity Electric Fields Delivered By Intratumoral Modulation Therapy, Andrew Deweyert, Erin Iredale, Hu Xu, Eugene Wong, Susanne Schmid, Matthew O. Hebb

Anatomy and Cell Biology Publications

Introduction

Diffuse intrinsic pontine glioma (DIPG) is a high fatality pediatric brain cancer without effective treatment. The field of electrotherapeutics offers new potential for other forms of glioma but the efficacy of this strategy has not been reported for DIPG. This pilot study evaluated the susceptibility of patient-derived DIPG cells to low intensity electric fields delivered using a developing technology called intratumoral modulation therapy (IMT).

Methods

DIPG cells from autopsy specimens were treated with a custom-designed, in vitro IMT system. Computer-generated electric field simulation was performed to quantify IMT amplitude and distribution using continuous, low intensity, intermediate frequency stimulation parameters. …

Microglia Are Both A Source And Target Of Extracellular Cyclophilin A, Gurkiran Kaur Flora, Ryan S. Anderton, Bruno P. Meloni, Gilles J. Guillemin, Neville W. Knuckey, Gabriella Macdougall, Vance Matthews, Sherif Boulos

Health Sciences Papers and Journal Articles

Glioblastoma (GBM) are lethal primary brain tumours whose pathogenesis is aided, at least partly, via a pro-tumorigenic microenvironment. This study investigated whether microglia, a cell component of the GBM microenvironment, mediates pro-tumorigenic properties via the action of cyclophilin A (CypA), a potent secretable chemokine and cytoprotectant that signals via the cell surface receptor, CD147. To this end, intracellular and secreted CypA expression was assessed in human primary microglia and BV2 microglial cells treated with the endotoxin, lipopolysaccharide (LPS) and the oxidative stress inducer, LY83583. We report that human primary microglia and BV2 microglia both express CypA and CD147, and that …

An Inflammatory Landscape For Preoperative Neurologic Deficits In Glioblastoma., Amal Katrib, Hyun-Hwan Jeong, Nina L Fransen, Kristin S Henzel, Jeremy A Miller

Articles, Abstracts, and Reports

No abstract provided.

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma, Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, John L. Villano

Internal Medicine Faculty Publications

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax^®-L) to standard therapy for newly diagnosed glioblastoma.

Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months …

Cd151-Α3Β1 Integrin Complexes Are Prognostic Markers Of Glioblastoma And Cooperate With Egfr To Drive Tumor Cell Motility And Invasion, Pengcheng Zhou, Sonia Erfani, Zeyi Liu, Changhe Jia, Yecang Chen, Bingwei Xu, Xinyu Deng, Jose E. Alfáro, Li Chen, Dana L. Napier, Michael Lu, Jian-An Huang, Chunming Liu, Olivier Thibault, Rosalind Segal, Binhua P. Zhou, Natasha Kyprianou, Craig Horbinski, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based …

Notch Regulation Of Adam12 Expression In Glioblastoma Multiforme, Ala'a S. Alsyaideh

Masters Theses 1911 - February 2014

Glioblastoma is the most common malignant brain tumor, accounting for 17% of all primary brain tumors in the United States. Despite the available surgical, radiation, and chemical therapeutic options, the invasive and infiltrative nature of the tumor render current treatment options minimally effective. Recent reports have identified multiple regulators of glioblastoma progression and invasiveness. It has been demonstrated that ADAM12, A Disintegrin And Metalloproteinase encoded by ADAM12 gene, is over-expressed in glioblastoma and directly correlated with tumor proliferation. Additionally, dysregulation of the Notch signaling pathway has been implicated in the pathogenesis of many gliomas. Lastly, an evolving role of microRNAs, …

Novel Report Of Expression And Function Of Cd97 In Malignant Gliomas: Correlation With Wilms Tumor 1 Expression And Glioma Cell Invasiveness Laboratory Investigation, Archana Chidambaram, Helen L. Fillmore, Timothy E. Van Meter, Catherine I. Dumur, William C. Broaddus

Office of Research Faculty & Staff Publications

Object. The Wilms tumor 1 (WT1) protein—a developmentally regulated transcription factor—is aberrantly expressed in gliomas and promotes their malignant phenotype. However, little is known about the molecular allies that help it mediate its oncogenic functions in glioma cells.

Methods. The authors used short interfering RNA (siRNA) to suppress WT1 expression in glioblastoma (GBM) cells and evaluated the effect of this on GBM cell invasiveness. Gene expression analysis was then used to identify the candidate genes that were altered as a result of WT1 silencing. One candidate target, CD97, was then selected for further investigation into its role by suppressing …