• Login
    View Item 
    •   UTSW DSpace Home
    • UT Southwestern Electronic Theses and Dissertations
    • UT Southwestern Electronic Theses and Dissertations
    • View Item
    •   UTSW DSpace Home
    • UT Southwestern Electronic Theses and Dissertations
    • UT Southwestern Electronic Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Mechanisms of Sensitization to Chemotherapy in Non-Small Cell Lung Cancer

    Thumbnail
    View/Open
    Available after 1/14/2014 (9.683Mb)
    Date
    2012-07-20
    Author
    Greer, Rachel Marie
    Metadata
    Show full item record
    Abstract
    Lung cancer is the leading cause of cancer-related deaths world-wide for men and women, due in part to late detection of disease and inherent resistance to treatment. This body of work focuses on resistance to treatment, specifically chemotherapy and understanding ways to sensitize non-small cell lung cancers to existing chemotherapies. Using a large panel of non-small cell lung cancers, response to common platinum-based doublet chemotherapy was tested, and compared in a statistical fashion to each chemotherapy as a single agent, to understand the breadth of responses, and have a baseline of response to improve upon. The rest of this work endeavors to make chemotherapies more effective at tumor kill by targeting tumor specific alterations. One such targeted approach focused on miR337, and its ability to influence paclitaxel sensitivity through introduction of miR337 mimics and antagomiRs was evaluated using MTS based assays; increasing miR337 levels in moderately paclitaxel-sensitive or completely paclitaxel resistant cells sensitized the cells at least ten-fold to paclitaxel. Non-small cell lung cancers have frequent mutations in p53 (>80%). Targeting of the p53 promoter region with agRNAs, in p53-mutant containing cell lines induces cytotoxicity that is reminiscent of wild type p53 activity and is associated with large increases of the non-coding RNA lincRNAp21, and can cause large sensitizations to p53-dependent chemotherapies such as doxorubicin, indicating that these agRNAp53s could be of therapeutic importance in p53-mutant lung cancers. Re-engagement of the apoptotic pathway by a small molecule (JP1201) sensitizes non-small cell lung cancers to a variety of chemotherapies. Anti-mitotic chemotherapies have the most frequent sensitization across a large panel of non-small cell lung cancers, and the largest degree of sensitization by combination with JP1201, and this sensitization is dependent on activation of the ER stress pathway. Xenograft models using cell lines recapitulate the ability of JP1201 to sensitize non-small cell lung cancers to chemotherapy, indicating that combinations with JP1201 might be effective in patients.
    URI
    http://hdl.handle.net/2152.5/1025
    Collections
    • UT Southwestern Electronic Theses and Dissertations

    UT Southwestern Health Sciences Digital Library and Learning Center | 5323 Harry Hines Boulevard, Dallas, Texas 75390-9049
    Telephone 214-648-2001 | Email
    Library Home | UT Southwestern Home
    DSpace software copyright © 2002-2016  DuraSpace
    Contact Us | Send Feedback
    TDL
    Theme by 
    Atmire NV
     

     

    Browse

    All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    Login

    UT Southwestern Health Sciences Digital Library and Learning Center | 5323 Harry Hines Boulevard, Dallas, Texas 75390-9049
    Telephone 214-648-2001 | Email
    Library Home | UT Southwestern Home
    DSpace software copyright © 2002-2016  DuraSpace
    Contact Us | Send Feedback
    TDL
    Theme by 
    Atmire NV