All ETDs from UAB

Advisory Committee Chair

James M Markert

Advisory Committee Members

Steven L Caroll

Corinne E Griguer

Douglas R Hurst

Justin C Roth

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are rare but highly aggressive cancer of the peripheral nervous tissue. Median patient survival is approximately two years following diagnosis due in part to the ineffective options for treatment. As an alternative therapeutic approach to conventional radio- and chemotherapy, oncolytic herpes simplex viruses type-1 (oHSVs) have been proposed to treat MPNSTs. These oHSVs have been shown safe in clinical trials with associated tumor regression. However, there is evidence that resistance to the therapy should be anticipated in a subset of patients. Therefore, the goal of this dissertation has been to identify the primary obstacles to oHSV therapy in MPNSTs to guide their future therapeutic application and improve patient outcomes. Using a large panel of MPNST-derived cell lines, we have identified a spectrum of oHSV resistant and permissive phenotypes. Resistance to oHSVs has been attributed to (1) limited expression by the tumor of the cellular entry receptors which facilitate HSV-1 entry and (2) the ability of infected cells to launch an intrinsic antiviral response to inhibit viral replication. To determine if resistance to oHSVs in MPNSTs was explained by an insufficient level of entry receptors, we assessed expression of nectin-1, the major HSV-1 entry receptor, and viral yields in a panel of human MPNST tumor lines, however no significant associations were observed. Furthermore, nectin-1 overexpression in resistant MPNST cell lines did not confer an oHSV-sensitive phenotype suggesting that entry receptor expression does not limit a productive infection in MPNSTs. To test the hypothesis that intrinsic antiviral activation was the explanation for oHSV resistance, we studied the activation of protein kinase R (PKR) and signal transducer and activator of transcription-1 (STAT1) in response to oHSV. We observed that activation of PKR was common even in permissive cell lines. In contrast, activation of STAT1 occurred in only a subset of cell lines and was associated with poor viral productivity. Manipulation of this pathway further demonstrated that STAT1 signaling contributes to oHSV resistance. These results mark a new direction in oHSV research and may help to establish biomarkers and select adjuvant therapies that improve the therapeutic effect of oHSVs.

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