Evaluation of therapy for canine intracranial neoplasia using PAC-1, a novel and potent procaspase-3 activator

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.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

VMS - Pathobiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2018

Author dc:creator

• Schlein, Lisa Janelle

Contributors dc:contributor

• Fan, Timothy M.
• Driskell, Elizabeth
• Barger, Anne
• Hergenrother, Paul

• Cancer
• Brain cancer
• Intracranial neoplasia
• Canine neoplasia
• Human neoplasia
• Novel therapeutics
• First procaspase-activating compound (PAC-1)

Statement dc:rights

• Copyright 2017 Lisa J. Schlein

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/99088

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/99088