Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide
Brock J Sishc, Lianghao Ding, Taek-Keun Nam, Collin D Heer, Samuel N Rodman, Joshua D Schoenfeld, Melissa A Fath, Debabrata Saha, Casey F Pulliam, Britta Langen, Robert A Beardsley, Dennis P Riley, Jeffery L Keene, Douglas R Spitz, Michael D Story, Brock J Sishc, Lianghao Ding, Taek-Keun Nam, Collin D Heer, Samuel N Rodman, Joshua D Schoenfeld, Melissa A Fath, Debabrata Saha, Casey F Pulliam, Britta Langen, Robert A Beardsley, Dennis P Riley, Jeffery L Keene, Douglas R Spitz, Michael D Story
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).
Conflict of interest statement
Competing interests: D.P.R., J.L.K., and R.A.B. are employed by and hold equity interests in Galera Therapeutics Inc., which provided the Mn-pentaazamacrocyclic dismutase mimetic AVA used in this study. D.R.S. and M.D.S. have Sponsored Research Agreements supported by Galera Therapeutics Inc. in preclinical studies of AVA in cancer therapy. D.R.S. is a consultant/advisory board member for Galera Therapeutics. M.A.F., D.R.S., R.A.B., D.P.R., and J.L.K. are inventors on patent application PCT/US2017/030871 submitted by Galera Therapeutics LLC that relates to the combination of pentaazamacrocyclic dismutase mimetics with high dose per fraction radiation and with pharmacologic inhibitors of hydrogen peroxide metabolism for cancer treatment. R.A.B., D.P.R., and J.L.K. are inventors on patent application PCT/US2018/027588 submitted by Galera Therapeutics LLC that relates to the combination of pentaazamacrocyclic dismutase mimetics with high dose per fraction radiation, with immune checkpoint inhibitors, and with both checkpoint inhibitors and high dose per fraction radiation for cancer treatment. All other authors declare that they have no competing interests.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Source: PubMed