Abstract 5062: Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity

Abstract

Abstract Introduction: Avasopasem manganese (GC4419) is a selective superoxide dismutase mimetic which has recently completed a Phase 3 clinical trial (NCT03689712) demonstrating a significant reduction in the severity of oral mucositis in patients receiving standard cisplatin and radiotherapy for head and neck squamous cell carcinoma (HNSCC). Up to 66% of HNSCC patients experience ototoxicity from platinum-based chemotherapy, resulting in tinnitus and hearing loss. The analysis of clinical trial data also revealed that patients treated with GC4419 in addition to cisplatin (cis) and radiotherapy reported less tinnitus than those treated with standard therapy alone. The generation of reactive oxygen species has long been recognized as an important contributor to cis-induced hearing loss; therefore, we hypothesize that administration of GC4419 with cisplatin can prevent ototoxicity by scavenging superoxide. Results: Organotypic cultures using postnatal day 2 or 3 mouse cochlea were treated with cis 4 µM and 0.5, 2, or 4 µM GC4419 for 24 hours. The explants were then stained for anti-myosin-VIIa. Hair cells were counted, and it was determined that 4 µM cis was sufficient to cause a decrease in hair cell numbers and GC4419 dose as low as 2 µM protected against this biological endpoint. To assess the effects of GC4419 on hearing loss in vivo, CBA/CaJ mice were treated as follows: 5 mice (1 female, 4 males) received 3 mg/kg cis IP, 4 mice (2 males and 2 females) received vehicle, 3 mice (2 females, 1 males) received 10 mg/kg IP GC4419, and 5 mice (2 females, 3 males) were treated with GC4419 10 minutes prior to cisplatin injection. Cis and GC4419 were administered for four consecutive days followed by two days of GC4419. The animals were allowed 8 recovery days, with Normosol SQ and high calorie food administered, prior to a second repetition of the treatment cycle. This protocol for cis dosing was found to be lethal in three mice in the cisplatin only group. Auditory brainstem response testing was performed before and after treatment, revealing elevated hearing thresholds in cis treated mice but not in mice treated with GC4419 and cis. Additionally, the cis treatment group experienced greater weight loss than the mice treated with GC4419 and cis Separately, in an H1299 tumor xenograft model in nu/nu mice, GC4419 5 mg/kg IP BID over 14 days was shown not to interfere with, and in fact somewhat increased, the tumor growth delay with cis 5 mg/kg IP QW x 3. Conclusion: These results support the hypothesis that treatment with the SOD mimetic GC4419 can reduce cis induced ototoxicity by scavenging superoxide and justify further studies to determine if this mechanism based approach can be implemented in cancer therapy. (Supported by a sponsored research agreement between the University of Iowa and Galera Therapeutics, Inc.) Citation Format: Keegan A. Christensen, Osama Tarabichi, Sei Sho, Hidaly Hernández, Bryce Hunger, Melissa A. Fath, Jeffery Keene, Robert Beardsley, Marlan Hansen, Douglas R. Spitz. Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5062.