ABS 042: Biomarker-based efficacy of oncolytic herpes virus therapy for the treatment against NF1- associated malignant peripheral nerve sheath tumor

Shraddha Potti ¹ , Lukmanul Hakkim Farruck ¹ , Christopher Stehn ¹ , David Largaespada ¹ , Robert Galvin ¹

¹ Masonic Cancer Center at University of Minnesota

Van Wickle (2025) Volume 1, ABS 042

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in individuals with Neurofibromatosis Type 1. The polycomb repressive complex 2 negatively regulates gene expression via trimethylation of histone 3.3 (H3K27me3), and its loss of function characterizes high-grade MPNST. Oncolytic herpes simplex virus (oHSV) represents a novel treatment avenue, but host cell repression of viral replication is a resistance mechanism. We hypothesize that PRC2 loss, characteristic of MPNST, enhances susceptibility to oHSV, as transcriptional silencing of viral replication may be dysregulated.

Methods: MPNST cell lines were infected with the oncolytic virus HSV-G47∆ in vitro, with multiplicities of infection (MOI) ranging from 3 to 0. Cell viability was assessed via MTS assay after 6 days. The half-maximal inhibitory concentration was determined by non-linear regression in GraphPad Prism. All experiments included three biological replicates.

Results: HSV-G47∆ demonstrated activity across all tested MPNST cell lines at MOI < 1.0. Pharmacologic inhibition of PRC2 did not affect HSV-G47∆ activity in the PRC2-deficient S462-TY but enhanced susceptibility in PRC2-proficient MPNST724 cells. S462-TY was engineered to express wild-type SUZ12 to restore PRC2 function under a tetracycline-controlled transcriptional activation system. Following confirmation of H3K27me3 restoration via Western blot with doxycycline exposure, PRC2 proficiency in this add-back model increased resistance to HSV-G47∆. Finally, cell viability assays were conducted in murine syngeneic MPNST models. The PRC2 deficient QmSC-NCS model was most sensitive while QmSC-N was resistant.

Discussion: Our results demonstrate that PRC2 status may serve as a biomarker for HSV- G47∆ sensitivity in MPNST, providing a therapeutic direction. Future experiments include mechanistic evaluation of our results with methylation assays and planned in vivo trials.