Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide

Abstract

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).

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

“…GC4419, a highly stable low molecular weight MnPAM dismutase mimic, is a selective superoxide dismutase mimic that has the characteristics of high cell permeability, high stability, and high selectivity to O 2 [ 91 ]. M40403 (GC4403) is the enantiomer of GC4419.…”

“…GC4419 combined with hyperfractionated radiotherapy can inhibit tumors in non-small cell lung cancer, pancreatic ductal adenocarcinoma, and head and neck squamous cell lines. Research using a radiation-resistant SqCC/Y1 HNSCC cell line and high-dose radiation (12 Gy per fraction) combined with GC4419 enhanced the response of tumors in SqCC/Y1 [ 91 ]. GC4419 increased the level of Bax in the lung tissue induced by IR, decreased the level of Bcl-2, and increased the ratio of Bax/Bcl-2.…”

Phytochemical Characterization of Taxus baccata L. Aril with Emphasis on Evaluation of the Antiproliferative and Pro-Apoptotic Activity of Rhodoxanthin

“…Hydrogen peroxide was also described as a selective killer of the cancer cells while being harmless to the normal cells, due to their mechanisms of defense. Hence, the synergy was demonstrated between a natural enzyme-like product that converts superoxide dismutase to hydrogen peroxide and radiotherapy in the treatment of various tumors [ 48 ].…”

Two-Year Tumor Outcomes of a Phase 2B, Randomized, Double-Blind Trial of Avasopasem Manganese (GC4419) Versus Placebo to Reduce Severe Oral Mucositis Owing to Concurrent Radiation Therapy and Cisplatin for Head and Neck Cancer

“…In addition, cancer cells are sensitive to hydrogen peroxide produced by avasopasem. In fact, in nonclinical studies, avasopasem synergized with high dose per fraction radiation through generation of high levels of hydrogen peroxide (10). The combined modality appeared to have strong efficacy against xenograft tumors in mouse models but was not cytotoxic to nonneoplastic cells.…”