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Identification of Targeted Therapeutics for Malignant Peripheral Nerve Sheath Tumors

Johansson, L. Gunnar
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1216841242

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders, affecting 1 in 3,500 worldwide. The hallmark of NF1 is the expression of benign tumors of the peripheral nerve (neurofibromas). In addition, patients have a 5-13% life time risk of developing malignant peripheral nerve sheath tumors (MPNST), a soft tissue sarcoma with poor prognosis. NF1 functions as a negative regulator of active RAS; and elevated levels have been observed in both the neurofibromas and MPNST. The levels of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) signaling are also increased in MPNST. In an attempt to define treatment options, we have treated MPNST cell lines grown as xenografts in nude mice, with the mTOR inhibitor RAD001 and the EGFR tyrosine kinase inhibitor erlotinib. When treatment was initiated prior to the formation of the tumors, RAD001 prevented the growth of the tumors and erlotinib reduced tumor growth by 35%. In already established tumors, erlotinib had no effect. RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. To find additional drugs that can target NF1 related tumors, we have recently screened NF1 related and sporadic MPNST cell lines using a high throughput screening approach. The only known difference between these tumors is the absence of NF1, and the upregulation of active RAS levels. Drugs that show selectivity against the NF1 related MPNSTs are likely to target pathways directly affected by NF1 and could potentially be used in both neurofibromas and MPNST.
Nancy Ratner, PhD (Advisor)
Robert Brackenbury, PhD (Committee Member)
Susan Waltz, PhD (Committee Member)
W. Sean Davidson, PhD (Committee Member)
James Fagin, MD (Committee Member)
147 p.
Cellular Biology
Neurofibromatosis type 1; NF1; MPNST; mTOR; Cancer

Recommended Citations

Citations

  • Johansson, L. G. (2008). Identification of Targeted Therapeutics for Malignant Peripheral Nerve Sheath Tumors [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1216841242

    APA Style (7th edition)

  • Johansson, L.. Identification of Targeted Therapeutics for Malignant Peripheral Nerve Sheath Tumors. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1216841242.

    MLA Style (8th edition)

  • Johansson, L.. "Identification of Targeted Therapeutics for Malignant Peripheral Nerve Sheath Tumors." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1216841242

    Chicago Manual of Style (17th edition)

ucin1216841242
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© 2008, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.