Abstract B079: The glycogen synthase kinase-3β inhibitor 9-ING-41 in combination with chemoimmunotherapy provides long-term survival in the Th-MYCN mouse model

Abstract BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children. Survival rates of children with high-risk disease are ∼50%, reducing to 10% for relapsed/refractory disease, highlighting the need for more effective treatments. Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase, highly expressed in cancers including neuroblastoma. In addition to its well-established role in driving cell growth and proliferation, there is increasing evidence suggesting a role in supporting tumor immune evasion. 9-ING-41 (Elraglusib), a GSK-3β inhibitor with clinical activity in adult cancers, is effective as a single agent in neuroblastoma animal models, and is currently in Phase 1/2 clinical trial in pediatric patients with refractory malignancies (NCT04239092). However, the efficacy of 9-ING-41 in combination with current clinically relevant chemotherapy and chemoimmunotherapy neuroblastoma protocols that include anti-GD2 antibody for high-risk patients, has not been established. AIMS: To establish, in the Th-MYCN mouse model of neuroblastoma, clinically relevant chemoimmunotherapy treatment protocols that include anti-GD2 antibody (14G2a), and to evaluate whether and how 9-ING-41 enhances their efficacy. METHODS: Efficacy and pharmacokinetic studies were performed in Th-MYCN mice. Th-MYCN tumor cells were allografted into fully immunocompetent versus immunocompromised mouse strains. RESULTS: Th-MYCN mice relapsed within 60 days following treatment with 2 consecutive daily doses of temozolomide/irinotecan (TEMIRI) or cyclophosphamide/topotecan (CYCLO/TOPO), in addition to 15µg 14G2a on day 1 and day 5. Pharmacokinetics of radiolabelled 14G2a confirmed that this regimen resulted in equivalent 14G2a serum levels in tumor-bearing Th-MYCN mice as observed for Dinutuximab in neuroblastoma patients. Addition of 9-ING-41 to TEMIRI or 14G2a alone, or combined TEMIRI/14G2a, delayed tumor growth in a dose-dependent manner, resulting in significantly extended survival compared to mice receiving the same treatments without 9-ING-41. 6/10 mice treated with TEMIRI/14G2a/70 mg/kg 9-ING-41 were long-term tumor-free survivors at 1 year of age (P<0.0001). Similar results were obtained for CYCLO/TOPO. TEMIRI/9-ING-41 was significantly more effective against Th-MYCN allografts injected into wild-type littermates than when the same cells were injected into immunocompromised NSG mice, suggesting that a fully functional immune system is required to achieve the highest efficacy of this combination. Together with the observation that 9-ING-41 alone enhanced the efficacy of anti-GD2 antibody, this data also suggests that 9-ING-41 exerts part of its potentiating role through boosting anti-tumour immunity. CONCLUSIONS: 9-ING-41 in combination with chemoimmunotherapy is highly potent, resulting in long-term tumor-free survival in the Th-MYCN mouse model of neuroblastoma. Our data suggests that 9-ING-41 at least in part works through modulating anti-tumour immunity, and we are currently investigating this further. Citation Format: Jayne Murray, Klaartje Somers, Crystal Mak, Stephanie Alfred, Jennifer Brand, Evon Poon, Nicholas Fletcher, Pei Li, Kristofer Thurecht, Juliet Gray, Andrew DJ. Pearson, Louis Chesler, Michael D. Hogarty, Francis Giles, Jamie Fletcher, David S. Ziegler, Murray D. Norris, Michelle Haber. The glycogen synthase kinase-3β inhibitor 9-ING-41 in combination with chemoimmunotherapy provides long-term survival in the Th-MYCN mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B079.