EXTH-12. CYTOCHROME C OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA

Sam Gary; Vincent Laufer; Kaysaw Tuy; Kyung-Don Kang; Claudia Oliva; Corinne Griguer; Anita Hjelmeland; Gregory Friedman

doi:10.1093/neuonc/noad179.0866

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EXTH-12. CYTOCHROME C OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA

Abstract

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EXTH-12. CYTOCHROME C OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA

Sam Gary, Vincent Laufer, Kaysaw Tuy, Kyung-Don Kang, Claudia Oliva, Corinne Griguer, Anita Hjelmeland and Gregory Friedman

Neuro-oncology (Charlottesville, Va.), Vol.25(Supplement_5), pp.v226-v226

11/10/2023

DOI: 10.1093/neuonc/noad179.0866

PMCID: PMC10639798

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10639798/pdf/noad179.0866.pdfView

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Abstract

Abstract RATIONALE Outcomes for patients with high-grade glioma (HGG) are dismal despite standard of care surgical resection, radiation, and temozolomide (TMZ) chemotherapy. RESULTS from our Phase I trial of pediatric patients with recurrent HGG suggest oncolytic herpes simplex virus-1 (oHSV) is safe with promising efficacy. However, optimization of oHSV therapy is needed to achieve more durable responses. Based on our prior work with matched pair HGG cell lines and patient-derived xenografts (PDXs) with and without acquired TMZ resistance, oHSV efficacy is enhanced in TMZ-resistant cells with no difference in oHSV entry receptor (CD111) expression. Microarray transcriptomic data of four PDXs with and without TMZ resistance revealed downregulation of interferon (IFN) responses. Cytochrome c oxidase subunit 4 isoform 1 (COX4I1) is expressed in recurrent HGG samples and cell lines. While COX4I1 positively regulates influenza virus replication, no study has investigated the role of COX4I1 in mediating oncolytic virotherapy efficacy. HYPOTHESIS We hypothesized that COX4I1 expression mediates HGG sensitivity to oHSV through suppression of IFN signaling. METHODS Using previously published models, oHSV cytotoxicity was assessed in vitro using Alamar Blue and CellTiter-Glo assays. oHSV infectivity and CD111 protein expression was assessed by flow cytometry. COX4I1 protein expression was measured by immunoblot. mRNA expression of IFN-stimulated genes was assessed by qPCR. RESULTS COX4I1 overexpression increased oHSV cytotoxicity and infectivity compared to empty vector controls. Short hairpin RNA knockdown of COX4I1 decreased oHSV cytotoxicity and infectivity in TMZ-resistant cells compared to pLKO controls. IFN-stimulated genes IFNB1, TMEM173, DDX58, IFIH1, and OAS1 were all significantly decreased in COX4I1 overexpressing cells and TMZ-resistant cells compared to parental lines. CONCLUSIONS Overexpression of COX4I1 sensitizes HGG cells to oHSV, and COX4I1 knockdown de-sensitizes TMZ-resistant HGG cells to oHSV, suggesting a novel role of COX4I1 in mediating HGG sensitivity to oHSV.

Details

Title: Subtitle: EXTH-12. CYTOCHROME C OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA
Creators: Sam Gary - University of Alabama at Birmingham
Vincent Laufer - University of Michigan
Kaysaw Tuy - University of Alabama at Birmingham
Kyung-Don Kang - University of Alabama at Birmingham
Claudia Oliva - University of Alabama at Birmingham
Corinne Griguer - University of Iowa
Anita Hjelmeland - University of Alabama at Birmingham
Gregory Friedman - University of Alabama at Birmingham
Resource Type: Abstract
Publication Details: Neuro-oncology (Charlottesville, Va.), Vol.25(Supplement_5), pp.v226-v226
DOI: 10.1093/neuonc/noad179.0866
PMCID: PMC10639798
ISSN: 1522-8517
eISSN: 1523-5866
Language: English
Date published: 11/10/2023
Academic Unit: Radiation Oncology
Record Identifier: 9984512060002771

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