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Sivak-Sears, Niccole R.The Acute-Phase Response and Cancer Risk
Doctor of Philosophy, The Ohio State University, 2003, Public Health
This dissertation contains three investigations that evaluate hypotheses concerning associations between the acute phase response (APR) and cancer. The APR is a coordinated sequence of systemic and metabolic changes occurring in response to acute and chronic stimuli, including pathogens, injury, and cancer. The goal of the first investigation (chapter 2) was to determine whether the previously observed associations between serum antioxidant and ferritin concentrations and cancer risk are actually attributable to the effect of the APR (caused by the pre-existing cancer) on serum antioxidant and ferritin levels. Individuals with 1) a prior cancer diagnosis, 2) previous heart attack, and 3) neither a history of cancer nor heart attack, had similar serum antioxidant levels so the question of whether the APR is responsible for the decrease of serum antioxidants observed in cancer patients could not be addressed. However, individuals in the cancer and heart attack groups with the highest APRs showed higher serum ferritin levels and lower serum iron levels than did individuals with the highest APRs in the group without these diseases. These findings suggest that the APR is responsible for differences in serum ferritin and serum iron levels among the three groups. The second investigation (chapter 3) evaluated the association between the chronic inflammatory condition, periodontal disease, and risk of lung cancer. We found no association between periodontal disease and lung cancer risk in women. Among men, a statistically significant trend of an increase in lung cancer risk with increasing periodontal disease severity was observed (p=0.0008), however this risk was restricted to smoking males; nonsmoking males showed no association between periodontal disease and lung cancer risk. These findings indicate either a modifying effect of smoking on gum disease or residual confounding by smoking. The third investigation (chapter 4) evaluated the association between use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) and adult glioblastoma multiforme risk. Self-reported glioblastoma multiforme cases were less likely than controls to report use of at least 600 pills of all types of NSAIDs combined during the ten year pre-diagnostic period. Findings were consistent for aspirin, ibuprofen, and naproxen/other NSAIDs, as well as for acetaminophen.

Committee:

Judith Schwartzbaum (Advisor)

Keywords:

Acute-Phase Response; Inflammatory Response; Cancer Risk; Lung Cancer; Serum Antioxidants; Serum Ferritin; Periodontal Disease; NSAIDs; Glioblastoma Multiforme

Young, Nicholas AdamInfluence of Sphingosine 1-Phosphate receptor subtypes on glioblastoma multiforme malignant behavior
Doctor of Philosophy, The Ohio State University, 2007, Integrated Biomedical Science
Cellular accumulation of Sphingosine 1-phosphate (S1P) stimulates cellular motility, invasion, proliferation, adhesion, and angiogenesis. S1P tranduces these cellular effects by signaling through one of a family of high affinity G-protein coupled receptors that include EDG-1/S1P1, EDG-5/S1P2, EDG-3/S1P3, EDG-6/S1P4, and EDG-8/S1P5. Upon receptor stimulation, unique and preferential G-protein signaling pathways are activated to varying degrees to elicit these cellular responses. Enzymatic production of S1P is a result of the activity of sphingosine kinase (SK). Expression of this protein has been shown to correlate to poor glioblastoma multiforme (GBM) patient prognosis. This deadly neoplasm is diagnosed through histologic criteria that include significant neovascularization, high mitotic index, and diffuse infiltrative appearance. Although progress has been made in the treatment of many cancers in recent years, the dismal patient prognosis for GBM patients has not. Mo lecular based therapies targeting the infiltrative nature of this tumor could ultimately improve patient outcome. This work focuses on GBM malignant behavior as influenced by S1P receptor subtype signaling. All the individual receptor subtypes were found to have unique influences over in vitro GBM proliferative, migratory, adhesive, and invasive responses. The S1P2 receptor subtype displayed novel S1P-induced pro-invasive, but anti-migratory effects, which were mediated through increased adhesion to the extracellular matrix. Invasiveness was promoted through CCN1, uPA, and uPAR, which have all been correlated to GBM tumorigenesis. S1P induced expression of CCN1 through S1P1-2 promoted invasion that was limited with antibody in a spheroid invasion assay. Enhanced activation of SK with receptor subtype S1P1 overexpression resulted in endogenous upregulation of uPA and uPAR expression as well as uPA activity. Additionally, antibody targeting uPA also limited total invasiv e distance of spheroids. The invasive mediators uPA and uPAR were shut down with the inhibition of SK and spheroid invasiveness was eliminated regardless of receptor subtype overexpression. The results of this work better delineate the complex S1P receptor subtype signaling pathways in GBM cells as well as their contributions to malignant behavior. The results on GBM invasiveness have illustrated the key role that SK plays and validated uPA and CCN1 as viable targets for molecular based approaches to therapy.

Committee:

James Van Brocklyn (Advisor)

Keywords:

sphingosine 1-phosphate; glioma; glioblastoma multiforme; invasion; sphingolipids; cancer

Qutaish, Mohammed QCRYO-IMAGING ASSESSMENT OF IMAGING AGENT TARGETING TO DISPERSING AND METASTATIC TUMOR CELLS
Doctor of Philosophy, Case Western Reserve University, 2014, Biomedical Engineering
The goal of this work is to create a platform methodology consisting of cryo-imaging experimental methods and specialized image analysis software to provide unique 3D, quantitative characterization of tumor models, including spread via dispersal and metastasis, and assessment of imaging agent targeting to dispersed tumor cell and metastatic tumor. Analyses used microscopic, 3D cryo-imaging which has the sensitivity to detect fluorescently labeled single cells over large volumes of tissues. Specifically, tumor cell dispersal in Glioblastoma multioforme (GBM) and micrometastases in breast cancer mouse models were detected, quantified, and visualized. Targeting of the fluorescently labeled SBK2 peptide to GBM dispersing cells, and CREKA peptide multiplexed Gd-MR probe to breast cancer metastases, were analyzed. For GBM tumor cell dispersal analyses in cryo-images, algorithms were developed to detect blood vessels, dispersing tumor cells, white matter tract and main tumor mass, as well as measure cell dispersal distance. Multiple GBM cell lines were characterized to find those that showed high dispersive patterns similar to the human disease. Software was created to assess how far from the main tumor mass, SBK2 efficiently labeled dispersing cells. Results showed that LN-229 and CNS-1 cell lines are highly dispersive, and cells mainly dispersed along blood vessels and white matter tract. Dispersal distance was as far as 562µm in LN-229 and >3mm in CNS-1. Fluorescently labeled SBK2 peptide labeled more than 99% of dispersing cells, and as far as 3.5 mm. For breast cancer metastasis analyses, software was created to quantify number and size of metastases using cryo-imaging volumes. Multimodality 3D deformable image registration was employed to register MRI and cryo-imaging volume. This enabled the validation of CREKA peptide targeting in MRI using the high resolution cryo volumes, and provided information about limitation and efficiency of the developed MRI agent. The 4T1 cell line was used to create a metastatic breast cancer model. Results showed an average of 156 metastases in cryo-volumes ranging in size of 0.1–8mm in diameter. Metastases were mainly found in lungs, liver, bones and adrenal gland. Rose criterion showed >73% of micrometastases in lungs were labeled by the MRI CREKA. Results were shown visually and quantitatively. Analysis methods and software demonstrated in the thesis should be applicable to a wide range of studies of cancer, imaging agents and theranostics.

Committee:

David Wilson (Advisor); Susann Brady-Kalnay (Committee Member); Lu Zheng-Rong (Committee Member); Andrew Rollins (Committee Member); Zhenghong Lee (Committee Member)

Subjects:

Biomedical Engineering

Keywords:

Cryo imaging; Glioblastoma multiforme; imaging agent; cell dispersal; metastatic tumor; image registration

Karkare, SwagataDirect inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses Glioblastoma growth
MS, University of Cincinnati, 2013, Pharmacy: Pharmaceutical Sciences
Glioblastoma multiforme (GBM) is the most common and, simultaneously, most aggressive form of primary brain tumor occurring in human adults. Despite clinical application of various chemotherapy regimens, radiation, and surgical approaches, the median survival of patients after GBM diagnosis does not exceed 15 months. This underscores the urgent need for development of new synthetic or naturally-derived therapeutic agents, which not only extend median survival beyond 15 months but also offer the potential for cure. Recent advances in delineating the contributions of distinct signaling pathways and genetic alterations in tumorigenesis offer new therapeutic targets for pharmacological interventions in GBM patients. For centuries, medicinal plants were used as essential sources for the discovery of new anticancer agents. However, to rise to the level of clinically valuable adjuvants in cancer patients, it is imperative to understand the mechanisms of action associated with plant extracts or individual components purified from medicinal plants. Using contemporary molecular biology techniques, the results from this study demonstrate that pharmacologically active ingredients present in the ethanol-soluble fraction of Azadirachta Indica (Neem) leaves (Azt), including nimbolide, induce significant cytotoxicity against GBM cells in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S border in GBM cells expressing the EGFRvIII oncogene, which is present in about 20-25% of glioblastomas. Azt directly inhibited kinase activity of the cyclin-dependent kinases CDK4/CDK6 leading to hypophosphorylation of the retinoblastoma (RB) protein and cell cycle arrest at G1-S. Independent of RB hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of GBM cells by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, Erk1/2 and STAT3, respectively. In contrast, mTOR and other cell cycle regulators were not affected by Azt. Following intratumoral injection of Azt using a subcutaneous mouse GBM xenograft model, initiation and glioblastoma growth were significantly reduced as compared to ethanol treated controls. Taken together, our findings demonstrate that Azt and nimbolide effectively suppress growth of glioma cells in vitro and in vivo through interference with vital cell cycle regulators such as RB. These findings suggest that nimbolide may offer substantial clinical benefit for GBM patients and, thereby, holds incredible promises for future clinical studies.

Committee:

Giovanni Pauletti, Ph.D. (Committee Chair); Biplab Dasgupta, Ph.D. (Committee Member); Gerald Kasting, Ph.D. (Committee Member)

Subjects:

Oncology

Keywords:

Ethanolic Neem leaf extract;Azadirachta indica;Neem;Glioblastoma Multiforme;Anticancer;Natural products

Uppalapati, PraneethNetwork Mining Approach to Cancer Biomarker Discovery
Master of Science, The Ohio State University, 2010, Computer Science and Engineering

With the rapid development of high throughput gene expression profiling technology, molecule profiling has become a powerful tool to characterize disease subtypes and discover gene signatures. Most existing gene signature discovery methods apply statistical methods to select genes whose expression values can differentiate different subject groups. However, a drawback of these approaches is that the selected genes are not functionally related and hence cannot reveal biological mechanism behind the difference in the patient groups.

Gene co-expression network analysis can be used to mine functionally related sets of genes that can be marked as potential biomarkers through survival analysis. We present an efficient heuristic algorithm EigenCut that exploits the properties of gene co-expression networks to mine functionally related and dense modules of genes. We apply this method to brain tumor (Glioblastoma Multiforme) study to obtain functionally related clusters. If functional groups of genes with predictive power on patient prognosis can be identified, insights on the mechanisms related to metastasis in GBM can be obtained and better therapeutical plan can be developed. We predicted potential biomarkers by dividing the patients into two groups based on their expression profiles over the genes in the clusters and comparing their survival outcome through survival analysis. We obtained 12 potential biomarkers with log-rank test p-values less than 0.01.

Committee:

Kun Huang, PhD (Committee Chair); Raghu Machiraju, PhD (Committee Member)

Subjects:

Bioinformatics; Computer Science

Keywords:

Biomarker; Gene co-expression networks; Glioblastoma Multiforme; Network mining; Biological networks

Williams, Shanté PatriceThe Role of Glycogen Synthase Kinase in Glioblastoma Multiforme Migration and Invasion
Doctor of Philosophy, The Ohio State University, 2011, Integrated Biomedical Science Graduate Program

Glioblastoma multiforme is the most common and severe form of malignant brain cancer accounting for 23% of all primary brain tumors. A hallmark of malignant brain tumors is the ability to infiltrate into the surrounding tissue, leading to subsequent tumor re-growth after surgery. Currently there are no anti-invasive therapies targeting migrating tumor cells or the signaling pathways responsible for the migratory process. Recently published data shows that pharmacological inhibitors of GSK-3 (glycogen synthase kinase-3), lithium chloride, AR-A014418 and SB415286, are effective in blocking glioma cell migration. GSK-3 is a serine/threonine protein kinase that plays a role in numerous signaling pathways and biological processes including insulin, growth factor, and nutrient signaling, cell fate specification during embryonic development, cell polarity in astrocytes, as well as an emerging role in cell motility. GSK-3 regulation is complex - in growth factor signaling GSK-3 becomes inactivated by phosphorylation and in Wnt signaling GSK-3 inactivation occurs via altered protein interactions leading to the stabilization of β-catenin, and the transcription of Wnt responsive genes. This work reports on a class of GSK-3 inhibitors, the indirubins, and their effects on both glioblastoma cell migration.

Indirubins potently blocked both glioblastoma migration and invasion. In gliomas, indirubins inhibited GSK-3 more than lithium as assessed by β-catenin TCF/LEF luciferase reporter assays and were effective at much lower concentrations than other GSK-3 inhibitors so far tested. When examined in animal xenograft models, treatment with 6-bromo-indirubin acetoxime (BIA) led to decreased tumor growth in both flank and intracranial tumors and an increase in survival. Histological examination of tumors showed a substantial decrease in blood vessel density in tumors in the flank and the brain (50% and 30% respectively), and a 40% reduction in invasion of the brain. Finally, this study shows that indirubins block motility of endothelial cells in vitro, and cause increased production of anti-angiogenic proteins. This data suggests that GSK-3 inhibitors may not only inhibit invasion of tumor cells, but also block angiogenesis, providing a new treatment paradigm for invasive gliomas.

Finally, the highly migratory nature of glioma cells highlights the need to identify the genes altered in glioma migration. A novel in vitro glioma migration model was recently described in which synthetic polymers of polycaprolactone promoted glioma cell motility when in an aligned configuration. Using this novel model, a large number of alterations were identified in the transcriptome of migrating cells. These included upregulation of known pro-motility genes, as well as EGF ligands (HB-EGF) and various cytokines including IL-11. These changes suggested that STAT3 may be a common downstream mediator of these transcriptional alterations. Knocking-down STAT3 activation using various STAT3 inhibitors slowed migration on aligned fibers. These data describe a novel pathway involved in glioma migration and suggest further targets for pharmacologic intervention.

Committee:

E. Antonio Chiocca, MD/PhD (Committee Co-Chair); Sean E. Lawler, PhD (Committee Co-Chair); Christopher Phiel, PhD (Committee Member); James Van Brocklyn, PhD (Committee Member)

Subjects:

Biomedical Research; Molecular Biology

Keywords:

Glioblastoma Multiforme; Cell Migration/Invasion; GSK-3; &946;-catenin

Fu, Andrew SongAffinity-based Delivery and Reloading of Doxorubicin For Treatment of Glioblastoma Multiforme
Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering
A reloadable drug delivery implant would allow for customizable chemotherapy tailored to the tumor progression of the individual patient. We report, for the first time, a polymer implant engineered to not only provide controlled delivery of an anticancer drug doxorubicin, but also to serve as a sponge that can absorb additional doses if needed. Numerous analytical methods were employed to characterize the affinity between doxorubicin and our affinity-based polymers consisting of cyclodextrin. Drug release and reloading were controlled by specific and reversible interactions between doxorubicin and cyclodextrin. Polymer synthesis conditions were optimized in vitro to ensure sufficient and fast-acting reloading in vivo. When implanted in a human brain tumor xenograft model in nude mice, our reloadable drug delivery platform enhanced the efficacy of localized chemotherapy. These results reflect the effectiveness of reloadable affinity-based polymers for providing local, flexible, and long-term treatment for cancer.

Committee:

Horst von Recum (Committee Chair)

Subjects:

Biomedical Engineering

Keywords:

affinity-based drug delivery; glioblastoma multiforme,

Aljohani, Hashim M.Signaling Pathways Associated with Gefitinib Resistance in Glioblastoma Multiforme (GBM)
MS, University of Cincinnati, 2014, Medicine: Molecular Genetics, Biochemistry, & Microbiology
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. The majority of GBM tumors show a mutated or overexpressed EGFR. However, the kinase domain mutations that usually correlate with response to the tyrosine kinase inhibitors in other cancers are infrequent in glioblastomas and phase II trials of the tyrosine kinase inhibitor (TKI), gefitinib showed no survival benefit in glioblastoma. Furthermore, tumors treated with the TKIs will inevitably recur highlighting the need to identify signaling pathways involved in GBM resistance to TKIs. To this end, we treated GBM cells that over express EGFR with increasing concentrations of Gefitinib and isolated resistant clones. These resistant clones were subject to RNAseq and the expression of several genes was found to be upregulated in these clones. These genes are all tyrosine kinase receptors and include ROS1, DDR1 and PDGFRA. The upregulation of these genes was confirmed at the protein level by western blot. Treatment with ROS1 inhibitors in ROS1 overexpressing clones led to sensitization of these clones to gefitinib. Our current study led to the discovery of alternative pathways used by GBM cells to evade cell death following treatment with gefitinib and identifies new therapeutic targets to prevent GBM cell resistance to the drug.

Committee:

El Mustapha Bahassi, Ph.D. (Committee Chair); Edmund Choi, Ph.D. (Committee Member); Peter Stambrook, Ph.D. (Committee Member)

Subjects:

Surgery

Keywords:

Glioblastoma multiforme;EGFR;tyrosine kinase inhibitor;GBM resistance to TKIs;Gefitinib;ROS1

Suh, Sung-SukA STUDY OF MICRORNAS ASSOCIATED WITH MULTIPLE MYELOMA PATHOGENESIS AND MICORRNAS/TP53 FEEDBACK CIRCUIT IN HUMAN CANCERS, MULTIPLE MYELOMA AND GLIOBLASTOMA MULTIFORME
Doctor of Philosophy, The Ohio State University, 2012, Biochemistry Program, Ohio State
MicroRNAs (miRNAs) are single-stranded RNAs of 19-25 nucleotides in length and play a crucial role in regulating gene expression though post-transcriptional gene silencing which leads to mRNA degradation or translational repression. Recently, miRNAs are increasingly implicated in regulating cancer initiation and progression. Here, we first tried to understand the roles of miRNAs in the pathogenic progress of multiple myeloma (MM), a plasma cell malignancy. In profiling assay of miRNA expression in MM cell lines and CD138+ bone marrow plasma cells (PCs) from subjects with MM, monoclonal gammopathy of undetermined significance (MGUS), and normal donors, we identified overexpression of miR-21, miR-106b-25 cluster, miR- 181a and b in MM and MGUS samples with respect to healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17-92 cluster, were shown to down regulate expression of SOCS-1. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR-106b-25 cluster, miR-181a and b. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis. Next, we investigated the role of miRNAs in the p53 regulatory loop in human cancers, especially, Mutiple Myeloma (MM) and Glioblastoma Multiforme (GBM). In multiple myeloma (MM), we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. On the other hand, in human Glioblastom (GBM) two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs via p53-dependent, negative regulation of their transcriptional regulators, E2F1 and MYC. In addition, they result in p53 accumulation by directly targeting MDM2 and TSC1, negative regulators of p53 and the mTOR pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Significantly, overexpression of transfected miR-25 and-32 in GBM cells inhibited growth of the GBM cells in mouse brain in vivo. Altogether, these results define microRNAs as positive regulators of p53 underscoring their role in tumorigenesis in MM and GBM.

Committee:

Carlo M Croce, MD (Advisor); Kay Huebner, PhD (Committee Member); Deborah S Parris, PhD (Committee Member); Samson T Jacob, PhD (Committee Member)

Subjects:

Biology

Keywords:

microRNA; TP53; Multiple Myeloma; Glioblastoma Multiforme