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

    Browse

    All of TUScholarShareCommunitiesDateAuthorsTitlesSubjectsGenresThis CollectionDateAuthorsTitlesSubjectsGenres

    My Account

    LoginRegister

    Help

    AboutPoliciesHelp for DepositorsData DepositFAQs

    Statistics

    Display statistics

    Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    TETDEDXWagner-temple-0225E-132 ...
    Size:
    5.691Mb
    Format:
    PDF
    Download
    Genre
    Thesis/Dissertation
    Date
    2018
    Author
    Wagner, Jessica Michelle
    Advisor
    El-Deiry, Wafik S.
    Committee member
    Graña-Amat, Xavier
    Golemis, Erica
    Haines, Dale
    Yang, Xiaolu
    Department
    Cancer Biology & Genetics
    Subject
    Biology
    Pharmacology
    Cancer Biology
    Drug Discovery
    Preclinical Studies
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/4005
    
    Metadata
    Show full item record
    DOI
    http://dx.doi.org/10.34944/dspace/3987
    Abstract
    ONC201 is a novel compound that upregulates endogenous TNF-Related Apoptosis-Inducing Ligand (TRAIL), in tumor and normal cells, restoring autocrine and paracrine anti-tumor activity within tumor cells, and upregulates the DR5 gene by activating the integrated stress response, inducing eIF2-alpha-dependent ATF4 and CHOP [1-3]. ONC201 also demonstrates potent anti-tumor effects on colorectal cancers [4, 5]. ONC201 presented a promising oral bioavailability, wide distribution throughout the body, and ability to cross the blood-brain barrier. Further, the unique ability of its TRAIL-and-DR5-based signaling to induce apoptosis in cancer cells and not normal cells adds to its appeal as an anti-cancer therapeutic and prompted clinical development [1-4, 6]. ONC201 has successfully completed an FDA advanced Phase I/II clinical trial in advanced aggressive refractory solid tumors. Results indicated that ONC201 is well-tolerated and recommended a phase II dose of 625 mg orally every 3 weeks. Several Phase I/II clinical trials are enrolling in multiple solid tumors and hematological malignancies [7, 8]. Chapter two of this study provides evidence that ONC201 dose intensification demonstrates an increased pharmacodynamic effect and an increasing anti-tumor efficacy in vivo while having a safe toxicity profile upon weekly dosing. This data influenced the Phase II clinical trials, which have now been adjusted to include weekly dosing. Given the potential anti-metastatic effects of TRAIL signaling and the role of TRAIL in the immune surveillance of cancer, we hypothesized that ONC201 would suppress metastatic tumor development and engage the immune system in its anti-cancer activity. We also establish that ONC201 provides an important anti-metastatic effect in CRC that should be pursued in both pre-clinical and clinical studies. Tail vein and surgical CRC models demonstrate that ONC201 inhibits the number and size of metastases. Evidence has shown that TRAIL can also inhibit cancer metastasis by possibly inducing cell death or TRAIL-sensitization in the primary tumor when cells undergo extravasation upon detachment from the primary tumor [9-11]. While we show that TRAIL plays a role in ONC201’s ability to inhibit migration/invasion in vitro, further investigation of the role of TRAIL in vivo is necessary. Our data indicates that ONC201 promotes a pro-immune response in CRC subcutaneous tumors with increased NK cells that play a role in ONC201’s efficacy in syngeneic models. Since activated natural killer cells express TRAIL, we established that ON201 can activate and induce TRAIL expression in NK cells [12, 13]. As we did not find any immune infiltrates in the metastases, we suggest that the effect of the micro-environment or in more clinically-relevant models with stromal environments should be pursued. Chapter 3 of this of thesis demonstrates the characterization of ONC201’s core structure and development of ONC201 analogues including their mechanistic differences and potential in vivo efficacy and safety. We have demonstrates the importance of the angular structure of ONC201 to ONC201’s anti-tumor efficacy [14]. The novel pharmacophore has now been called as imipridone and is essential for its anti-tumor activity, as the linear isomer had no anti-tumor effect. We leveraged this unique pharmacophore to synthesize ONC201 analogues with distinct therapeutic properties; namely, targeting ONC201-resistant tumor types or possessing distinct signaling properties. Imipridone R2 analogues have a lower IC50 and are more promising than their lead compound in certain tumor types. ONC212, a halide R2 analogue, demonstrates superior efficacy in vivo in melanoma xenografts, a large therapeutic window; but does have a rapid PK. Oncoceutics is currently developing ONC212 for a first-in human Phase I clinical trial. The fourth chapter of this study demonstrates the potential of a combinational therapy with ONC201 in colorectal cancer with bevacuzimab. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. ONC201 in combination with bevacuzimab led to superior results with almost no tumor growth. This result was re-capitulated in syngeneic models. Given that bevacuzimab is approved for metastatic CRC, we suggest that ONC201 in combination with bevacuzimab should be introduced into a combinatorial Phase II clinical trial. This thesis focuses on the importance of dose-intensification of ONC201 on its pre-clinical efficacy; establish an anti-metastatic effect; demonstrate an immune increase in subcutaneous models; and elucidate the role of the core angular structure in efficacy with the development novel ONC201 analogues. The importance of pre-clinical studies, ONC201’s analogues including the successful development of ONC212, and potentially advantageous combinational therapies with anti-angiogenics is explained in the chapters throughout.
    ADA compliance
    For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
    Collections
    Theses and Dissertations

    entitlement

     
    DSpace software (copyright © 2002 - 2021)  DuraSpace
    Temple University Libraries | 1900 N. 13th Street | Philadelphia, PA 19122
    (215) 204-8212 | scholarshare@temple.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.