Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Lombardi Comprehensive Cancer Center
    • Program of Tumor Biology
    • Graduate Theses and Dissertations - Tumor Biology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Lombardi Comprehensive Cancer Center
    • Program of Tumor Biology
    • Graduate Theses and Dissertations - Tumor Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Novel Relationships of Splicing Factors and Regulation in TMZ-Resistant Glioblastoma

    Cover for Novel Relationships of Splicing Factors and Regulation in TMZ-Resistant Glioblastoma
    View/Open
    View/Open: Tiek_georgetown_0076D_14302.pdf (58.MB) Bookview

    Creator
    Tiek, Deanna Marie
    Advisor
    Riggins, Rebecca B
    Abstract
    Glioblastoma (GBM) is a devastating cancer, due to both our narrow understanding of its molecular drivers and limited therapeutic strategies. The blood-brain barrier (BBB) limits the chemotherapeutic options for the treatment of GBM, but the DNA-damaging agent temozolomide (TMZ) can penetrate the BBB and is the first-line standard of care treatment together with surgery and radiation for this tumor. However, most patients’ tumors rapidly become resistant to TMZ, and TMZ-resistant GBM is uniformly fatal. The overall premise of my thesis research was to identify strategies for the second-line treatment of GBM through the study of models and mechanisms of TMZ resistance. To this end, I established two TMZ-resistant GBM cell line pairs. Molecular and phenotypic characterization these GBM TMZ- resistant cell lines indicated that one, 42MGBA-TMZ, captured the “grow” of the “go or grow” model for GBM-resistance. By contrast, the second, 8MBGA-TMZ, exhibited increased in migration, encompassing the “go” aspect of TMZ resistance. One potential mechanistic driver of TMZ resistance is alternative splicing, as the brain contains the most alternatively spliced transcripts of any organ, and the GBM tissue exhibits the deregulated expression of some splicing factors compared with healthy brain tissue. The orphan nuclear receptor - estrogen-related receptor beta (ERRβ) expresses multiple isoforms, and using the 42MGBA-TMZ and 8MBGA-TMZ, I assessed the expression and function of two ERRβ isoforms - ERRβ short form (ERRβ-sf) and ERRβ-2 in GBM. Although ERRβ is an orphan nuclear receptor with no known endogenous ligand, the synthetic agonist DY131 can potently activate the receptor. Previous studies have shown ERRβ-2 to be pro-apoptotic when activated by DY131. I therefore used in silico and in vitro methods to determine proteins required for the expression of the pro-apoptotic ERRβ-2 isoform. I found that the serine/arginine (SR) rich splicing factor SRSF6may function in the generation of the ERRβ-2 isoform, and that inhibition of cdc2-like kinases (CLKs, which phosphorylate SR proteins) with TG-003 in combination with the ERRβ synthetic agonist DY-131 potently inhibits GBM cell migration and growth in vitro. Overall, these studies add two new cell lines to the limited repertoire of TMZ-resistant GBM cell culture models and begin to define the importance of studying ERRβ isoform function and switching as a potential
     
    strategy to target TMZ-resistant GBM cells.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1055184
    Date Published
    2019
    Subject
    Brain cancer; Drug resistance; Glioblastoma; Glioma; Nuclear receptors; Temzolomide; Cytology; Cellular biology;
    Type
    thesis
    Embargo Lift Date
    2020-07-05
    Publisher
    Georgetown University
    Extent
    149 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Thumbnail

      Informed Consent for Obstetric Anesthesia Research Factors That Influence Patients' Decisions to Participate 

      Dorantes, Deanna M.; Tait, Alan R.; Naughton, Norah N. (2000-08)
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility