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.

    A Systems Approach to Understand the Molecular Synergy of Combined mTOR/Histone Deacetylase (HDAC) Inhibition in the Treatment of Cancer

    Cover for A Systems Approach to Understand the Molecular Synergy of Combined mTOR/Histone Deacetylase (HDAC) Inhibition in the Treatment of Cancer
    View/Open
    View/Open: Simmons_georgetown_0076D_12489.pdf (22.MB) Bookview

    Creator
    Simmons, John Kyle
    Advisor
    Mock, Beverly A
    Abstract
    The clinical necessity of combining molecularly targeted agents to effectively treat cancer is clear. At the molecular level, the limitations of single-target inhibition due to the complexity and redundancy of oncogenic signaling networks has been well demonstrated. High-throughput chemical and functional genomic approaches have identified potential combinations with synergistic effects on tumor cell viability and proliferation. Yet, elucidation of how these combinations cooperate in the context of highly complex oncogenic networks remains challenging. A multifaceted approach at the cellular and organismal level was taken to evaluate the synergistic activity of combining mTOR and HDAC inhibitors. Promising evidence of activity and synergy was observed in high-throughput matrix dose-response screening of large human cancer cell line libraries, in vivo testing in a genetically-engineered mouse (GEM) model, traditional xenografts, and in ex vivo treated patient samples. In a GEM myeloma model, a conservative mTORi/HDACi treatment regimen significantly improved overall survival compared to vehicle or single agents, with median survival increased by 3 months. We then developed a network-driven approach to identify synergistic activity of the combination at the molecular level on critical oncogenic regulators. Co-expression analysis of cells treated individually and in combination identified a distinct network of cooperatively targeted genes. We evaluated the cooperative network for differential expression between normal and malignant cells, as well as for correlation with survival in a large patient dataset. 37 cooperatively affected genes were both differentially expressed in MM and predictive of survival (p
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/709952
    Date Published
    2014
    Subject
    Cancer; Drug Combinations; HDAC Inhibitors; mTOR Inhibitors; Multiple Myeloma; Pharmacology; Cytology; Pharmacology; Cellular biology;
    Type
    thesis
    Embargo Lift Date
    2016-08-15
    Publisher
    Georgetown University
    Extent
    198 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
    Metadata
    Show full item record

    Related items

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

    • Cover for Regulation of cadherin-11 by GSK3 inhibition and TGFbeta1 treatment in cancer
      cells

      Regulation of cadherin-11 by GSK3 inhibition and TGFbeta1 treatment in cancer cells 

      Farina, Anne Kata. (Georgetown University, 2008)
    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