Abstract A145: Restoring p53 function with novel synthetic mRNA therapy to inhibit growth of TP53-mutant tumors in synergy with taxane agents

Abstract TP53, which encodes the tumor suppressor protein p53, plays a pivotal role in regulating cell cycle and apoptosis. Mutations in TP53 are a major oncogenic driver across diverse cancer types, significantly impacting tumor progression and patient prognosis. Various strategies have been explored to restore wild-type p53 function, including small molecules targeting specific p53 mutants, inhibition of negative regulators to prevent p53 degradation, and delivery of wild-type p53 via adenoviral vectors. However, these approaches are often limited by the heterogeneity of p53 mutations and suboptimal therapeutic efficacy. Herein, we introduce an optimized synthetic mRNA-based therapeutic platform designed to restore p53 function in cancers with high TP53 mutation frequencies. Key elements of the Hanmi p53 mRNA—including the tailored 5′ and 3′ untranslated regions (UTRs), the optimized open reading frame (ORF), and Hanmi’s proprietary 5′ capping reagent—were refined to enhance expression and stability. We assessed its therapeutic potential using both in vitro and in vivo models derived from p53-mutant cancers, including lung, ovarian, and other tumor types. Our results show that Hanmi’s p53 mRNA therapy selectively suppressed proliferation of p53-mutant cancer cells by inducing apoptosis and cell cycle arrest. In vivo xenograft studies demonstrated significant tumor growth inhibition in lung, ovarian, and pancreatic cancer models, with no adverse effects on mouse body weight. Furthermore, in a clinically relevant orthotopic cancer model, the therapy exhibited potent antitumor activity. Moreover, the combination of p53 mRNA therapy with Abraxane resulted in markedly enhanced tumor regression with complete responses, highlighting the synergistic potential of this therapeutic strategy. In the taxane-resistant in vitro model of cancer, Hanmi p53 mRNA therapy effectively inhibited cancer cell growth regardless of taxane resistance. These findings demonstrate the Hanmi p53 mRNA therapy as a novel and effective approach for targeting TP53-mutant cancers both as a single agent or in combination along with taxane as well as overcoming taxane resistance, offering new avenues for precision oncology. Citation Format: Seung-Hyun Shin, Yong Ho Heo, Youngjin Han, Sol-Bi Shin, Innah Kim, Soye Jeon, Aran Park, Jooyun Byun, Daejin Kim, In Young Choi. Restoring p53 function with novel synthetic mRNA therapy to inhibit growth of TP53-mutant tumors in synergy with taxane agents [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 A146.