Abstract 667: The radioprotector GC4419 ameliorates radiation induced lung fibrosis while enhancing the response of non-small cell lung cancer tumors to high dose per fraction radiation exposures

Abstract

Stereotactic Ablative Radiotherapy (SAbR) has revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite these advances, treatment-limiting normal tissue toxicities preclude the use of fully potent radiation prescriptions in large or centrally located tumors. Radiation-induced lung fibrosis (RILF), thought to be generated by the production of superoxide in irradiated tissues, is a natural target for agents to limit RILF and thus allow for fully potent SAbR. Superoxide dismutase (SOD) catalyzes the conversion of superoxide into hydrogen peroxide, which then may be converted to water and oxygen via catalase, protecting normal cells from oxidative damage. GC4419 (Galera Therapeutics, St. Louis, MO), a selective small molecule SOD-mimetic acts as both a protector and mitigator of radiation-induced superoxide damage. A single pretreatment with GC4419 significantly reduced the fibrotic density of focally irradiated murine lung tissue (54 Gy, single dose). Furthermore, daily post-irradiation (54 Gy, single dose) use of GC4419 also increasingly reduced lung fibrosis based upon the total duration of daily delivery. Since tumor protection could be a concern, animals with H1299, A549, and HCC827 lung tumor xenografts were treated with GC4419 30 minutes prior to the tumors being irradiated with a single 18 Gy dose, followed by 4 additional daily doses of GC4419. Tumor growth was significantly delayed (p = 0.0022) with the majority of mice apparently tumor-free at X days. Similar enhancements in tumor radiation response were seen with syngeneic lung (LLC) and breast (4T1) tumor models. Subsequent Tumor Cure Dose (TCD50) assays demonstrated that GC4419 enhanced the efficacy of radiation by a factor of 1.67. The dose enhancement seen with GC4419 was associated with the size of the dose per fraction, and if the single 18 Gy dose fractionation scheme was altered to include the biologically equivalent dose schedules of daily irradiations of 2 Gy for 16 days, 4.8 Gy for 5 days, 7.3 Gy for 3 days, or 9.9 Gy for 2 days, the radiation enhancing properties of GC4419 were more pronounced as the dose per fraction increased. Our hypothesis that the tumor response was driven by the overwhelming and persistent production of H2O2 is supported by the fact that the GC4419-enhanced radiation response of tumors derived from H1299CAT cells (doxycycline-driven catalase overexpressing), and treated accordingly with doxycycline, is completely abrogated. These findings suggest that GC4419 not only displays clinical potential as a normal tissue radiation protector and mitigator, but has the additional advantage of enhancing SAbR. Citation Format: Brock J. Sishc, Elizabeth Polsdofer, David A. Bloom, Collin Heer, Douglas R. Spitz, Debabrata Saha, Michael D. Story. The radioprotector GC4419 ameliorates radiation induced lung fibrosis while enhancing the response of non-small cell lung cancer tumors to high dose per fraction radiation exposures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 667.

Superoxide Dismutase as an Intervention for Radiation Therapy-Associated Toxicities: Review and Profile of Avasopasem Manganese as a Treatment Option for Radiation-Induced Mucositis

“…Also, like M40403, Sishc has demonstrated that avasopasem is effective at preventing and mitigating radiation normal tissue toxicity in mouse models of radiation-induced pulmonary fibrosis and oral mucositis. 46 , 47 Intriguingly, these reports also suggest potential for avasopasem in the particularly refractory setting of reirradiation. In addition, the question of whether older cancer patients are more susceptible to treatment toxicities has been ongoing for many years, with potential relevance in HNC radiation therapy given the age of some patients.…”

“…Mitigation of any supportive care indication which is based on the protection of normal cells from a cytotoxic challenge comes with the hypothetical risk that tumor tissue may also be protected. Earlier animal model studies have suggested that avasopasem not only does not decrease the anti-cancer efficacy of radiation, but with higher dose per fraction can increase it substantially 46 and, while simultaneously protecting the mucosa can enhance tumor kill following radiation and immunoradiotherapy. 47 In 2020, Anderson reported that long-term follow-up of Phase 2b participants confirmed that GC-4419 did not negatively impact tumor response (overall survival, progression-free survival, locoregional control, distant metastases) one and two years 55 , 56 following treatment.…”