Author ORCID Identifier

17349885

Date of Graduation

5-2020

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Balveen Kaur

Committee Member

Ji Young Yoo

Committee Member

Joya Chandra

Committee Member

Rachael Sirianni

Committee Member

Tae Jin Lee

Abstract

Integrins are known to play an important role in activating multiple intracellular pathways, one of which is focal adhesion kinase (FAK). Phosphorylation of FAK can lead to the activation of various downstream signaling pathways that can increase tumor cell growth and proliferation, making it an ideal target for cancer therapeutics. Due to the fact that many FAK inhibitors are limited in their penetration of the blood brain barrier, we investigated the use of Penfluridol, an antipsychotic drug known to attenuate integrin expression at a transcriptional level, in combination with oncolytic herpes simplex I virus (oHSV) in a glioblastoma model. We examined the effects of oHSV on FAK signaling by looking at FAK phosphorylation at different time points post-infection and saw that FAK was activated by viral infection at earlier time points. When combining Penfluridol with oHSV, we saw that at higher drug concentrations there was a decrease in viral propagation, however combination treatment increased overall tumor cell killing compared to either treatment alone. Additionally, we know that viral treatment causes immune cell infiltration leading to viral clearance. Combination of Penfluridol with virus treatment significantly reduced immune cell migration towards infected cells. To assess the effects of Penfluridol in vivo, GBM tumors were implanted intracranially in mice and treated with Penfluridol and oHSV. Survival data and bioluminescence imaging to evaluate virus replication was collected to examine the efficacy of the combination treatment. Overall, virus replication was not inhibited by Penfluridol treatment in vivo. Furthermore, mice treated with both Penfluridol and oHSV survived significantly longer than mice in individual treatment groups. These findings conclude that Penfluridol has the ability to attenuate integrin and FAK signaling and increase tumor cell killing when combined with oHSV in vitro. Additionally, we have seen that the combination treatment of Penfluridol and oHSV can significantly enhance survival in both immune deficient and immune competent mouse models in vivo.

Keywords

Penfluridol, oncolytic virus therapy, focal adhesion kinase (FAK), integrins, Glioblastoma (GBM), antipsychotic drug, integrin-FAK signaling, immune cell migration, brain-blood barrier, oHSV

Available for download on Thursday, April 08, 2021

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