Abstract LB478: Oncolytic herpes simplex virus enhances the anti-tumor response to radiation in human fusion-positive rhabdomyosarcoma patient derived xenografts

Field: Medicine (Health Sciences)

Abstract Introduction: Rhabdomyosarcoma (RMS) is a highly aggressive soft tissue tumor that accounts for 5% of all childhood cancers. Chromosomal translocations generating PAX-FOXO1 fusion genes characterize an aggressive RMS subtype, and children with fusion positive (FP)-RMS have the worst prognosis. Radiation therapy is a mainstay in the treatment of FP-RMS, but tumors often develop resistance to radiation, and children who do survive often suffer from long-term sequelae. These children will require innovative approaches to improve disease outcomes and the quality of life for survivors. FP-RMS cells often exhibit aberrant signaling in the interferon pathways and upregulated expression of viral entry receptors on the tumor cell surface, making them good targets for oncolytic viral (OV) therapy. In addition, OVs may hijack the metabolic and transcriptional dependencies created by fusion proteins promoting changes that may lead to decreased therapeutic resistance. In light of these findings, the current study evaluated the ability of a genetically engineered oncolytic (o)HSV, M002, to overcome radiation resistance in human FP-RMS PDX cells. Methods: Four human FP-RMS PDXs were established and maintained by orthotopic injection of 1 primary (MAST_473), and 3 recurrent (MAST_612, MAST_118, and MAST_213) patient-derived FP-RMS cells into the quadriceps femoris muscle of athymic nude mice. Tumors were dissociated and the cells treated with M002 (0.1- 50 plaque forming units (PFU) per cell), XRT (0-10 Gy) or both in combination using doses well below the calculated lethal dose 50% (LD50) concentrations. Viability was measured using colorimetric assays. Synergy was quantified employing the method of Chou-Talalay. Summary of results: MAST_612 and MAST_473 FP-RMS PDXs demonstrated resistance to XRT treatment as measured by no significant change in viability (calculated LD50 on post-treatment day 6: 44 and 34 Gy, respectively). Two PDXs derived from the recurrent human FP-RMS cells, MAST_118 and MAST_213 were sensitive to XRT showing LD50 of 0.5 and 2 Gy respectively, on post-radiation day 6. M002 showed a dose dependent cytotoxicity in MAST_118, MAST_213, MAST_473, and MAST_612 PDX cells with calculated LD50 values of &lt;1, 8, 17, and 24 PFU/cell, respectively, at 48 hours post-treatment. M002 enhanced the anti-tumor response to XRT in all the PDXs derived from the three recurrent human FP-RMS, and the combinations were synergistic. Combination therapy was not synergistic in the MAST_473 primary FP-RMS PDX cells. Conclusion: Treatment with M002 enhances the anti-tumor response to XRT in FP-RMS PDX cells. RNA sequence analysis of the FP-RMS PDX cells will assist in identifying the genetic footprint specific to FP-RMS tumor subtypes responsible for this response and identify specific subgroups of FP-RMS patients who may benefit from the addition of OV therapy to XRT. Citation Format: Maryam G. Shaikh, Morgan L. Brown, Nazia Nazam, Sorina Shirley, Louisa Markert, James Markert, Jamie M. Aye, Elizabeth A. Beierle. Oncolytic herpes simplex virus enhances the anti-tumor response to radiation in human fusion-positive rhabdomyosarcoma patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB478.