Cancer Biology Commons^™

Sdf-1Α Mediates Primary Tumor Escape In Glioblastoma Through Activation Of Mesenchymal Transitions., Charles T. Froman-Glover

College of Arts & Sciences Senior Honors Theses

Glioblastoma (GBM), a highly aggressive primary brain tumor originating in glial cells, poses a significant challenge due to its rapid growth and invasive nature within healthy brain tissue.

Current treatments involve surgical resection, chemotherapy, and radiation. These treatments alone are not enough to cure this disease, and a better understanding the mechanics of the tumor micro-environment is imperative to furthering the field of cancer research. This research focuses on understanding the tumor microenvironment's impact, specifically investigating the role of stromal cell-derived factor 1 (SDF-1) mechanics on GBM aggressiveness. SDF-1 is known to facilitate disease progression by facilitating chemotaxis toward the …

Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser

Electronic Theses, Projects, and Dissertations

Glioblastoma multiforme is the most aggressive type of glioma, demonstrating extremely low long-term survival despite modern therapies. Chimeric antigen receptor T cells have shown extreme levels of success in the treatment of B cell lymphomas through persistent anti-tumor activity. Prior research has demonstrated the therapeutic potential in targeting the C3a-C3aR1 pathway as it acts in an autocrine loop, maintaining the proliferation and survival of cancer stem cells within the tumor. Here, we reorient the treatment to target C3aR1 for the treatment of glioblastoma multiforme. In order to achieve this, Jurkat immortalized T cells will express various chimeric antigen receptor designs …

The Phenomenon Of Multidrug Resistance In Glioblastomas, Alexandr N. Chernov, Diana A. Alaverdian, Elvira S. Galimova, Alessandra Renieri, Elisa Frullanti, Ilaria Meloni, Olga V. Shamova

Hematology/Oncology and Stem Cell Therapy

The most common and aggressive brain tumor in the adult population is glioblastoma (GBM). The lifespan of patients does not exceed 22 months. One of the reasons for the low effectiveness of GBM treatment is its radioresistance and chemoresistance. In the current review, we discuss the phenomenon of multidrug resistance of GBM in the context of the expression of ABC family transporter proteins and the mechanisms of proliferation, angiogenesis, and recurrence. We focused on the search of molecular targets among growth factors, receptors, signal transduction proteins, microRNAs, transcription factors, proto-oncogenes, tumor suppressor genes, and their single-nucleotide polymorphisms.

Stem Cell-Based Therapies And Glioblastoma: A Seminal Matter, Kumaria Ashwin, Ashwin Kumaria

Hematology/Oncology and Stem Cell Therapy

No abstract provided.

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 …

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 …

Honokoil Treatment On Glioblastoma Cells, Julianne Weaver

Honors Theses

Glioblastoma is a malignant brain tumor without effective treatment options available because of its resistance to chemotherapy and radiation. This specific type of cancer is difficult to treat because the cancer stem cells that are not actively growing. These cells are dormant, which means they will not react to treatment because they are not dividing, and it is these cells that result in the high prevalence of relapse. Honokiol is a Chinese magnolia species that is known for its anti-inflammatory, anti-proliferative, and proapoptotic effects which make it an optimal candidate for glioma cell treatment. Honokiol was used in this experiment …

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 …

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 …

Wisp1 Is An Overexpressed Driver Of Glioblastoma, Pushan R. Dasgupta

Dissertations & Theses (Open Access)

Despite current multimodal therapies for glioblastoma (GBM) the prognosis remains very grim. There is a tremendous need to identify new genetic drivers which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor …

Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma, Yingxuan Chua

Dissertations & Theses (Open Access)

Gliomas are clinically challenging brain tumors with dismal survival rates due to its infiltrative nature and ineffective standard therapy. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the contributions of intracellular IGFBP2 to tumor development and progression are poorly understood. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via …

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 …

Elucidating The Igfbp2 Signaling Pathway In Glioma Development And Progression, Kristen M. Holmes

Dissertations & Theses (Open Access)

Diffuse gliomas are highly lethal central nervous system malignancies which, unfortunately, are the most common primary brain tumor and also the least responsive to the very few therapeutic modalities currently available to treat them. IGFBP2 is a newly recognized oncogene that is operative in multiple cancer types, including glioma, and shows promise for a targeted therapeutic approach. Elevated IGFBP2 expression is present in high-grade glioma and correlates with poor survival. We have previously demonstrated that IGFBP2 induces glioma development and progression in a spontaneous glioma mouse model, which highlighted its significance and potential for future therapy. However, we did not …

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, …

Role Of Transient Receptor Potential Canonical-6 (Trpc6) Channel In Metastasis Of Glioblastoma Multiforme, Rajarajeshwari Venkataraman

Electronic Theses and Dissertations

Glioblastoma multiforme (GBM) is one of the extremely fatal brain tumors. The main reason that makes it so lethal is its capability to invade and spread to other parts of CNS producing secondary tumors. Among other factors hypoxia, reduced oxygen availability, is linked to higher metastatic potential of cancers. Hypoxia causes numerous changes in genome and proteome of the cell. These changes help a normal cell to adapt to nutritional deficiency, but the same changes can increase the malignancy and metastasis in tumor cells. Extensive research by a number of curious scientists reveal that various pathways involving numerous proteins cross-talk …