Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide.
Brock J SishcLianghao DingTaek-Keun NamCollin D HeerSamuel N RodmanJoshua D SchoenfeldMelissa A FathDebabrata SahaCasey F PulliamBritta LangenRobert A BeardsleyDennis P RileyJeffery L KeeneDouglas R SpitzMichael D StoryPublished in: Science translational medicine (2021)
Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism. This synergy was abrogated by conditional overexpression of catalase in the tumors. In addition, in vitro NSCLC and mammary adenocarcinoma models showed that AVA increased intracellular hydrogen peroxide concentrations and buthionine sulfoximine- and auranofin-induced inhibition of glutathione- and thioredoxin-dependent hydrogen peroxide metabolism selectively enhanced AVA-induced killing of cancer cells compared to normal cells. Gene expression in irradiated tumors treated with AVA suggested that increased inflammatory, TNFα, and apoptosis signaling also contributed to treatment synergy. These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide-dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).
Keyphrases
- hydrogen peroxide
- radiation induced
- radiation therapy
- nitric oxide
- high dose
- clinical trial
- gene expression
- small cell lung cancer
- cell cycle arrest
- oxidative stress
- dna methylation
- squamous cell carcinoma
- locally advanced
- open label
- cell proliferation
- brain metastases
- rheumatoid arthritis
- cell death
- insulin resistance
- reactive oxygen species
- induced apoptosis
- cell therapy
- double blind
- randomized controlled trial
- mass spectrometry
- stem cell transplantation
- study protocol
- endoplasmic reticulum stress
- tandem mass spectrometry
- signaling pathway
- simultaneous determination
- phase ii