Opportunities and limitations for targeting hydrogen peroxide metabolism in cancer therapy: insights from soft tissue sarcoma and glioblastoma

Cancer is a lethal disease that threatens the lives of millions of Americans annually. Despite major advances in cancer treatments, patients still suffer due to inadequate response to therapy or highly toxic side effects after treatment. Hydrogen peroxide (H₂O₂) is a small molecule known for its common use in wound care. H₂O₂ is also present in the body as small amounts of it are required for normal function. When exposed to excess amounts of H₂O₂, non-tumor tissues can remove it to prevent toxicities. However, tumors generally are less efficient at removing H₂O₂. This project explored using H₂O₂ to enhance therapy in two types of rare cancers, glioblastoma (brain cancer) and soft tissue sarcoma (cancers of muscle, fat, nerve, and connective tissue). We showed that using the H₂O₂-generating compound, GC4419 (AVA), enhanced radiation therapy in soft tissue sarcoma cells. This effect was selective to sarcomas cells but not normal skin cells as sarcomas demonstrated reduced activity of the H₂O₂ removal enzyme GPx1. Moreover, AVA promoted wound healing in mice following radiation, thus preventing radiation wound healing impairment that occurs in nearly 30% of soft tissue sarcoma patients. In glioblastoma (GBM), high dose vitamin C was used to generate H₂O₂ in different subtypes of GBM and we found it improved response to chemoradiation in the treatment-resistant mesenchymal subtype, especially with increased dosing frequency in mice (3 days/week compared to 5 days/week).