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Targeting ß-catenin in MPNSTs

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2017, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that are a major cause of mortality of Neurofibromatosis type 1 (NF1) patients. MPNST patients have few therapeutic options available and only complete surgical resection can be curative. MPNST formation and survival are dependent on activated ß- catenin signaling. The goal of this study was to determine if inhibition of the CK2 enzyme can be therapeutically exploited in MPNSTs, given CK2’s role in maintaining oncogenic phenotypes including stabilization of ß-catenin. We found that CK2a is over expressed in MPNSTs and is critical for maintaining cell survival, as the CK2 inhibitor, CX-4945 (Silmitasertib), and shRNA targeting CK2a in vitro each significantly reduced MPNST cell viability. These effects were preceded by loss of critical signaling pathways in MPNSTs, including destabilization of ß-catenin and TCF-8. CX-4945 administration in vivo slowed tumor growth and extended survival time. We conclude that CK2 inhibition is a promising approach to blocking ß-catenin in MPNST cells, although combinatorial therapies may be required for maximal efficacy.
Nancy Ratner, Ph.D. (Committee Chair)
David A. Largaespada, Ph.D. (Committee Member)
Lionel Chow, M.D. Ph.D. (Committee Member)
Brian Gebelein, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
127 p.

Recommended Citations

Citations

  • Kendall, J. (2017). Targeting ß-catenin in MPNSTs [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin149155952770148

    APA Style (7th edition)

  • Kendall, Jed. Targeting ß-catenin in MPNSTs. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin149155952770148.

    MLA Style (8th edition)

  • Kendall, Jed. "Targeting ß-catenin in MPNSTs." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin149155952770148

    Chicago Manual of Style (17th edition)