Abstract 4330: Employing synthetic mRNA therapeutic platform to restore p53 function to suppress growth of p53 mutant cancer

Abstract TP53, a gene encoding p53, is a critical tumor suppressor gene, and its mutation serves as a major driver in various cancer types, deeply influencing tumor progression and patient prognosis. Efforts to restore wild-type p53 function have included targeting specific p53 mutants with small molecules, preventing p53 degradation through inhibition of its negative regulators, and employing adenoviral vectors to deliver wild-type p53. However, these strategies face challenges, including limited efficacy and the heterogeneity of p53 mutations. In this study, we present an optimized mRNA-based approach to restore p53 functionality, utilizing both in vitro and in vivo models of cancers with high p53 mutation frequencies. To enhance therapeutic efficacy, we optimized key elements of p53 mRNA, including the 5' and 3' untranslated regions (UTRs), the open reading frame (ORF), and Hanmi’s 5' capping reagent. Using cancer cell lines derived from lung, ovarian, pancreatic, and head and neck cancers harboring p53 mutations, we evaluated the therapeutic potential of our p53 mRNA therapy. Selectivity was assessed by examining its effects on both normal and p53 wild-type cancer cells. Our findings demonstrate that Hanmi’s p53 mRNA therapy selectively inhibits the proliferation of p53-mutant cancer cells by inducing apoptosis and cell cycle regulators such as PUMA, BTG2, and p21. Importantly, in vivo studies revealed significant tumor growth inhibition in xenograft models of lung, ovarian, and pancreatic cancers, with no notable impact on mouse body weight. Additionally, we tested the efficacy of our p53 mRNA therapy in a cancer orthotopic model, confirming its potent antitumor activity in a clinically relevant setting and demonstrating the selective efficacy against tumor. These results underscore the promise of p53 mRNA as a novel and efficient therapeutic strategy for selectively targeting p53 mutant cancers, paving the way for improved outcomes in precision oncology. Citation Format: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Sol-Bi Shin, Soye Jeon, Aran Park, Jooyun Byun, Daejin Kim, In Young Choi. Employing synthetic mRNA therapeutic platform to restore p53 function to suppress growth of p53 mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4330.