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Title:Evaluation of therapy for canine intracranial neoplasia using PAC-1, a novel and potent procaspase-3 activator
Author(s):Schlein, Lisa Janelle
Advisor(s):Fan, Timothy M.
Contributor(s):Driskell, Elizabeth; Barger, Anne; Hergenrother, Paul
Department / Program:Pathobiology
Discipline:VMS - Pathobiology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Brain cancer
Intracranial neoplasia
Canine neoplasia
Human neoplasia
Novel therapeutics
First procaspase-activating compound (PAC-1)
Abstract:Canine central nervous system tumors can develop deeply within the brain parenchyma, precluding surgical resection and limiting therapeutic options. PAC-1 is a novel, blood-brain barrier penetrant, pro-apoptotic small molecule activator of procaspase-3 (PC-3), with orphan drug status for the treatment of human glioblastoma multiforme. PC-3 is frequently overexpressed in malignantly transformed tissues, providing an opportunity to selectively induce apoptosis in cancer cells with dysregulated upstream apoptotic circuitry. This study evaluates the in vitro activity of PAC-1 against a panel of brain tumor cells, and the feasibility of combining PAC-1 with radiation therapy in an in vivo murine glioma model. Immunohistochemical characterization of PC-3 was performed in 21 normal canine brains and approximately 700 canine and human intracranial neoplasms. Murine, canine, and human glioma cell lines were evaluated for PC-3 expression and in vitro sensitivity to PAC-1 and radiation. PC-3 is overexpressed in canine intracranial neoplasms and high-grade human astrocytomas relative to normal brain tissues. Immortalized glioma cell lines show in vitro sensitivity to PAC-1 and radiation monotherapies at biologically relevant exposures. Murine gliomas appear to be sensitive to PAC-1 and radiation monotherapies, as well as to combination therapy with both PAC-1 and radiation therapy; however, murine study results are not statistically significant at this time. Investigation of therapeutic approaches that combine PAC-1 with radiation therapy and/or temozolomide will further elucidate its therapeutic potential in murine models and canine patients.
Issue Date:2017-07-14
Rights Information:Copyright 2017 Lisa J. Schlein
Date Available in IDEALS:2018-03-02
Date Deposited:2017-08

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