Medicine and Health Sciences Commons^™

Spatiotemporal Optimization Of Intratumoural Electric Field Modulation For Cancer Therapy, Erin Iredale

Electronic Thesis and Dissertation Repository

The use of anti-cancer non-ablative electric fields is an expanding area of research that includes clinically available external devices for the treatment of glioblastoma (GBM), and a pre-clinical internal system called Intratumoural Modulation Therapy (IMT). IMT uses multiple electrodes implanted within the tumour to apply low intensity electric fields (~1 V/cm) focused on the target region, anywhere in the brain, with no externally visible devices. In this thesis, multi-electrode spatiotemporally dynamic IMT is investigated through computer simulation, numerical optimization, brain phantom and in vitro validation methods. These planning and validation strategies are hypothesized to improve tumour coverage with the necessary …

The Effects Of Radiation On Cancer Stem Cells In Glioblastoma And Ovarian Cancer, Aaron Keniston

Electronic Theses, Projects, and Dissertations

High grade serous ovarian cancer (HGSOC) and glioblastoma multiforme (GBM) are some of the most aggressive forms of cancer with poor patient survival. Despite successful cancer therapies, these malignancies have high recurrence rates which can be attributed to cancer stem cells (CSC) due to innate tumor initiating properties. In this study, we investigated the response of CSC populations to proton and photon radiation by quantification of core stem cell transcription factors Sox2 and Oct4. This was carried out utilizing a Sox2/Oct4 green fluorescent protein based reporter designated as SORE6-GFP measured by flow cytometry. We hypothesize that proton and photon irradiation …

Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones

All ETDs from UAB

Treatment options for the universally lethal brain tumor, glioblastoma (GBM), are severely limited and often unsuccessful in fully eradicating the disease. Extremely aggressive in nature, GBM cells often implore suppressive mechanisms to evade therapeutic detection which aids in the dismal 15-month median survival rate. Facilitating disease severity and more importantly, disease recurrence, are the immunosuppressive and chemoresistant phenotypes of GBM cells. Specifically, the DNA alkylating agent, temozolomide (TMZ) possesses lymphodepleting properties shunting robust immune cell infiltration into an immunologically cold tumor microenvironment. Additionally, through inherent or acquired mechanisms, GBM tumors commonly become resistant to the DNA damaging effects of TMZ …

Challenges And Opportunities In Glioblastoma And Immunovirotherapy With Oncolytic Herpes Simplex Virus Type 1, Dagoberto Estevez-Ordonez

All ETDs from UAB

This dissertation covers data from published and pre-published studies exploring challenges and opportunities in the treatment of malignant glioma with emphasis in glioblastoma and oncolytic immunovirotherapy with an oncolytic herpes simplex virus type 1 (HSV-1) designed to induce expression of IL-12, M002 (murine IL-12) and M032 (human IL-12).It starts with the report of a study that uncovered important racial and socioeconomic disparities experienced by patients with glioblastoma treated in Alabama. Notable results also include the unexpected finding of increased survival in African American patients with glioblastoma even after controlling for factors associated with survival and socioeconomic disparities. The implications of …

Modeling Of Cns Cancer With A Focus On The Immune Component, Daniel Zamler

Dissertations & Theses (Open Access)

The knowledge surrounding cancers of the central nervous system remains poorly developed, in particular with regard to the immune component. The works contained in this thesis look at craniopharyngioma, glioblastoma, and several forms of brain metastasis. While some attention is given to the tumor cells themselves, as well as the patient setting which these studies model, the immune component of disease progression and treatment plays a strong role in each and is the primary focus of the works contained.

Craniopharyngioma is a relatively rare tumor in adults. Although histologically benign, it can be locally aggressive and may require additional therapeutic …

Restoring The Sphingolipid Balance In Glioblastoma, Cyntanna C. Hawkins

All ETDs from UAB

Glioblastoma (GBM) is a highly aggressive brain tumor with a median survival of 15 months even with standard of care—surgical resection, radiotherapy, and chemotherapy. Two of the key characteristics contributing to this malignancy are its highly invasive phenotype and resistance to the chemotherapy, temozolomide (TMZ). We, and others, have identified the sphingolipid balance as a driver of these phenotypes with dysregulated sphingolipid metabolism seen in GBM patient samples. The ceramidases, specifically acid ceramidase (ASAH1), mediate the balance between ceramides and sphingosine-1-phosphate (S1P). ASAH1 breaks down ceramides ultimately forming S1P. While ceramides induce cell death, S1P promotes migration and cell survival. …

Understanding The Protumorigenic Functions Of St6gal1 In Glioblastoma Stemness And Metabolism, Sajina Gc

All ETDs from UAB

Glioblastoma (GBM) is a rare but deadly cancer with median survival of just 15 months despite of aggressive treatment. Advancement in novel treatment modalities is hindered by its heterogeneous nature, which includes subsets of neural stem cell-like brain tumor initiating cells (BTICs) that are highly tumorigenic and therapy-resistant. bgalactoside a-2,6-sialyltransferase 1 (ST6Gal1) is elevated in most tumors including in normal and neoplastic stem cells. ST6Gal1 imparts oncogenic phenotypes such as invasion, apoptosis evasion, therapy resistance, TIC maintenance among others via sialylation of critical receptors like, Fas, TNFR1, EGFR and more. Yet ST6Gal1 led regulation of BTIC specific cell surface proteins …

Atrx Inactivation And Idh1-R132h Drive Preferential Sensitivity To Proton Vs. X-Ray Radiotherapy In Glioma Stem Cells, Ángel Adrián Garcés

Dissertations & Theses (Open Access)

Background: Glioma Stem Cells (GSCs) are self-renewable, treatment resistant cells in the glioma tumor mass known to promote tumor development. In contrast to traditional photon-based radiation therapy (XRT), proton radiation therapy (PRT) may induce more complex DNA damage and therefore might have the potential to eliminate GSCs. Although previous studies have individually linked IDH mutations, specifically IDH1^R132H, and ATRX inactivating mutations to improved patient outcomes and suppressed DNA damage repair compared to their respective wild-types, the mechanisms by which these two genetic alterations interact in GSCs treated with PRT compared to XRT are currently unknown. We hypothesize that …

A Novel In Vitro Model To Study Immune Interactions In Glioblastoma, Hasan Alrefai

All ETDs from UAB

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Despite decades of research, GBM has a median survival of approximately 14 months, necessitating the development of novel GBM therapeutics. The drug-development process has been hindered due to the lack of high-fidelity pre-clinical models. While in-vitro models of patient-derived xenografts (PDX) present an interesting approach to modeling GBM, they typically fail to incorporate the non-cancerous cells that support tumor growth and progression. Others have attempted to address this problem by using techniques such as 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they …

Alternative Splicing Of Anxa7 Dictates Receptor Tyrosine Kinase Fates In Glioblastoma, Sindhu Nair

All ETDs from UAB

Alternative splicing (AS) is a tightly regulated process essential for lineage specification in complex tissues like the brain. Dysregulated splicing in glioblastoma (GBM) is a mechanism exploited by tumor cells to retain or splice out exons consequently rewiring isoform-specific protein interactions to sustain tumor phenotypes. Receptor tyrosine kinases (RTK) amplifications are frequent events in GBM driving tumor growth and progression and are key targets for chemotherapy. However, RTK targeting in GBM has achieved limited success predominantly due to adaptive mechanisms of resistance in a constantly evolving tumor microenvironment. Clonal populations and crosstalk between RTKs sustain heterogeneity within a tumor leading …

Investigating The Metabolic Progression Of Glioblastoma With Hyperpolarized Magnetic Resonance, Travis Salzillo

Dissertations & Theses (Open Access)

Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma (GBM) can improve patient survival by providing physicians the time to optimally deliver treatment. This includes early in development, while the tumor is still manageable, or following initial therapy, when alternative treatments should be considered. The main goal of this project was to determine whether metabolic imaging with hyperpolarized magnetic resonance spectroscopy (MRS) could detect changes in tumor progression more rapidly than conventional anatomic magnetic resonance imaging (MRI) in patient-derived GBM murine models. To comprehensively capture the dynamic nature of cancer metabolism, in vivo pyruvate-to-lactate conversion with hyperpolarized MRI, …

Evaluating Soluble Axl As A Biomarker For Glioblastoma, Daniel Raymond

All NMU Master's Theses

AXL, a receptor tyrosine kinase, is known to promote malignant phenotypes in various types of cancer. AXL overexpression is commonly observed in glioblastoma and correlates with a worse prognosis. Detectable in most biological fluids, the extracellular domain of AXL, sAXL, is the product of enzymatic cleavage by ADAM10/17. Here we used ELISA, BCA and BCG assays to characterize blood serum from 23 newly diagnosed GBM patients which was collected roughly 24 hours before and after surgery as well as every three months post-surgery, corresponding to follow-up treatment visits. Immunoblotting was used to determine relative AXL expression in 13 patient tumor …

Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance, Soniya Bastola

All ETDs from UAB

Glioblastoma multiforme (GBM) is a highly invasive, highly vascularized, and heterogeneous malignant tumor of the brain. Due to the highly infiltrative phenotype of GBM, surgery often leaves behind residual tumor cells. In many cases, recurrence occurs close to the surgical margin suggesting the role of these remaining cells in promoting tumor aggressiveness. Rapidly growing tumor creates subsequent hypoxic, and hypovascular core due to limited nutrients, whereas tumor cells in the leading edge have access to nutrients from vasculature enriched microenvironment. Studies have identified the cellular and molecular heterogeneity between the tumors in core and edge. Still, their mechanisms of intercellular …

Exploring The Roles Of Long Non-Coding Rnas In Glioblastoma Tumor Recurrence And Therapy Resistance, Christian Tyler Stackhouse

All ETDs from UAB

ABSTRACT Glioblastoma (GBM) is the most common and devastating primary CNS brain tumor with a median survival time of around 14 months. Most patients succumb to re-current disease which is often more malignant than the primary tumor and is frequently therapy resistant. There have not been significant advances in the treatment of GBM despite decades of research. This is partly due to the lack of accurate preclinical models and of the focus on primary rather than recurrent tumors. We created a 350 gene custom GBM-specific panel which contains 16 molecular signatures including molecular sub-typing signatures. We have demonstrated concordance of …

Understanding And Targeting Glucose Transporter 3 In Glioblastoma, Catherine Jeanne Libby

All ETDs from UAB

Glioblastoma (GBM) is the most common adult primary malignant brain tumor with a median survival of about 15 months, even after aggressive treatment. Treatment of GBM is difficult for multiple reasons including the location of the tumor, tumor invasiveness, and the high degree of both inter-and intra-tumoral heterogeneity. Contributing to intratumoral heterogeneity are highly tumorigenic, stem-like tumor cells, with the capacity to self-renew and propagate the tumor, termed brain tumor initiating cells (BTICs). BTICs are also commonly therapy resistant, highly invasive, and metabolically plastic with elevated expression of glucose transporter 3 (GLUT3) allowing them to preferentially survive in low nutrient …

Acetylcholine Signaling In Glioblastoma Invasion And Peritumoral Hyperexcitability, Emily Grace Thompson

All ETDs from UAB

Glioblastomas are the most common and deadly form of primary brain cancer in adults. Current treatment strategies are aggressive, including a combination of surgical resection, radiotherapy, and chemotherapy. However, median patient survival has remained stagnant at 12 to 15 months for the last several decades. This dismal patient outcome has prompted efforts to understand the unique characteristics of these tumors, since traditional therapeutics have not been efficacious. Extensive invasion is a salient feature of glioblastomas that significantly diminishes the effectiveness of current treatment strategies and is ultimately the cause of tumor recurrence within 2 years in approximately 80% of patients. …

The Anti-Tumor Effects Of Hur Inhibition In Glioblastoma, Jiping Wang

All ETDs from UAB

Glioblastomas (GBMs) are the most malignant primary brain tumor. GBMs represent 14.7% of total primary CNS tumors and 47.7% of malignant CNS tumors. The median survival of GBM is 18-20 months, while five-year survival rate is only 5.6%. GBMs are maintained by glioma stem cells (GSCs), and poor treatment outcomes are linked to the high resistance of GSCs to radiation and chemotherapy, and the immunosuppressive tumor microenvironment. The mRNA binding protein HuR is a key regulator of tumor growth and development based upon the fact that HuR targets mRNAs that are broadly involved in tumorigenesis. We have previously shown that …

Marcks Effector Domain: Functions In Glioblastoma Progression And Novel Cytolytic Therapy, Nicholas James Eustace

All ETDs from UAB

Glioblastoma (GBM; grade IV astrocytoma) is the most common primary adult brain malignancy and remains incurable despite tremendous advances in our understanding of this heterogeneous disease. In this dissertation, we explore the challenges encountered in the treatment of GBM and discuss a promising new therapeutic approach gleaned from studies of the phospholipid binding “effector” domain (ED) of the protein Myristoylated alanine-rich protein C kinase substrate (MARCKS). Following an introduction to central nervous system (CNS) tumors and the grading of diffuse gliomas, we explain how recent advancements to our understanding of the cellular and molecular composition of CNS tu-mors, and the …

Analysis Of The Gtp Cyclohydrolase I/Tetrahydrobiopterin Pathway In Glioblastoma Biology, Anh Tran

All ETDs from UAB

Glioblastomas (GBMs) are the most common primary malignant brain tumors in adults and one of the most aggressive cancers with high rates of recurrence and therapeutic resistance. In GBMs, subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have the unique capacity to promote tumor maintenance, therapeutic resistance, and angiogenesis. Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and BTIC maintenance. GTP cyclohydrolase 1 (GCH1) is the rate limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in GBM. …

Microenvironmental Regulation And Epigenetic Control Of Glioma Pathogenesis, Nathaniel H. Boyd

All ETDs from UAB

Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor initiating cell hypothesis. The ischemic microenvironment characterized by low oxygen and glucose, and acidic stress occurs in both solid tumors and non-neoplastic tissue injury. Standard of care for glioblastoma (GBM) includes the chemotherapy temozolomide, which is not curative due, in part, to residual therapy-resistant brain tumor initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CAIX), a hypoxia and acidic stress responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we …

Towards Adaptive Radiotherapy Through Development Of Treatment Response Prediction, Anthony V. Lausch

Electronic Thesis and Dissertation Repository

Despite modern treatment advances, overall survival (OS) remains poor for many cancers such as liver and brain. Cancer is a fundamentally heterogeneous and adaptable disease and therefore personalized adaptive treatment strategies may be a key towards improving OS. Radiotherapy, a commonly used cancer treatment technique which employs ionizing radiation to kill tumours, holds promise for delivering adaptive treatment. However, effective adaptation requires the ability to assess and predict tumour treatment response. Therefore development of treatment response prediction tools represents a critical first step towards improving patient outcomes via treatment adaptation. The overall goal of this thesis is to develop treatment …

Cancer Stem Cells In The Screening Of Anticancer Drugs For Central Nervous System Tumors, Sarah Elizabeth Daron-Mathis

Theses, Dissertations and Capstones

There is a growing need (in the medical field) to design personalized therapy for cancer patients. Decades of cancer research have found no silver bullet that can cure all or even most patients. This study evaluated four patients affected by central nervous system (CNS) tumors (Ependymoma and Glioblastoma), and found that tumors with the same histology had unique responses to treatment. Each sample presented different levels of heterogeneity in expressed biomarkers and responded to drugs at varying levels.

Oncologists conventionally treat cancer patients with drugs tested in large clinical trials. However, often patients do not experience positive outcomes following treatments …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Molecular Characterization Of Glioblastoma Cancer Stem Cells, Jo Meagan Garner

Theses and Dissertations (ETD)

Malignant gliomas are locally aggressive, highly vascular tumors that have an overall survival time less than 14 months, and current therapies provide little improvement in the disease course and outcome. While glioblastoma multiforme (GBM) patients present uniform histological phenotypes, the molecular determinants of the disease vary considerably between individual cases resulting in complicated prognosis. The heterogeneity, aggressiveness and rapid tumor relapse of GBM is believed to be sustained by cancer stem-like cell populations that are able to initiate and maintain tumors. Although CSCs represent only a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance …

Mda-9/Syntenin: From Glioblastoma Pathogenesis To Targeted Therapy, Timothy P. Kegelman

Theses and Dissertations

The most common malignant glioma, glioblastoma multiforme (GBM), remains an intractable tumor despite advances in therapy. Its proclivity to infiltrate surrounding brain tissue contributes greatly to its treatment failure and the grim prognosis of patients. Radiation is a staple in modern therapeutic regimens, though cells surviving radiation become more aggressive and invasive. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/Syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in human melanoma models. We show that MDA-9/Syntenin is robustly …

Marcks Is A Regulator Of Growth, Radiation Sensitivity And Is A Novel Prognostic Factor For Glioblastoma Multiforme, John Jarboe

All ETDs from UAB

Glioblastoma multiforme (GBM) is the most common and deadly primary brain malignancy necessitating improved understanding of GBM biology. In this study, we explore the role of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) in the context of GBM. We have discovered that the MARCKS protein regulates GBM growth as well as response to radiation therapy through its effects on proliferation, senescence, and DNA repair based on our studies in cell culture and in patient-derived xenograft tumors implanted in mice. Importantly, our analysis of clinical patient data demonstrates that MARCKS is an independent predictor for outcome in GBM patients. Indeed, high MARCKS …

Taz As A Regulator Of Mesenchymal Transformation And Clinical Aggressiveness In Gliomas, Katrina Salazar

Dissertations & Theses (Open Access)

Glioblastoma multiforme (GBM) is an aggressive, high grade brain tumor. Microarray studies have shown a subset of GBMs with a mesenchymal gene signature. This subset is associated with poor clinical outcome and resistance to treatment. To establish the molecular drivers of this mesenchymal transition, we correlated transcription factor expression to the mesenchymal signature and identified transcriptional co-activator with PDZ-binding motif (TAZ) to be highly associated with the mesenchymal shift. High TAZ expression correlated with worse clinical outcome and higher grade. These data led to the hypothesis that TAZ is critical to the mesenchymal transition and aggressive clinical behavior seen in …

Effects Of Hyperthermia On Photochemical Internalization-Mediated Delivery Of Bleomycin, Christina Schlazer

UNLV Theses, Dissertations, Professional Papers, and Capstones

Standard treatment protocols for high-grade gliomas, such as glioblastoma multiforme (GBM), are highly ineffective due to their inability to eradicate infiltrating tumor cells. Improvements in overall survival are likely to be realized only with the development of more effective localized therapies capable of eradicating tumor cells in the surgical resection margin and beyond. Photochemical internalization (PCI) is a localized light-based therapeutic modality that enhances the efficacy of therapeutic macromolecules including chemotherapeutic agents such as bleomycin. A number of studies have shown that this photodynamic therapy (PDT) - based modality may prove effective in the treatment of high-grade gliomas.

Three-dimensional multicell …