Abstract 5696: Hanmi’s p53 mRNA and abraxane synergistically promote tumor control in PTX-prefered cancer through p53 stabilization

Abstract TP53 is the most frequently mutated tumor suppressor gene in human cancers and plays a critical role as a master regulator of apoptosis and cell cycle. Approximately 50% of human cancers harbor TP53 mutations, which are associated with accelerated tumor progression and resistance to anti-cancer therapies leading to unfavorable prognosis. As the way to restore the loss of function caused by p53 mutations, mRNA-based therapy is expected to yield novel therapeutic outcomes that remain unattainable with current approaches. This study endeavored to characterize the types of p53 mutations that exhibit heightened sensitivity to lipid nanoparticle (LNP)-encapsulated mRNA expressing wild-type p53. The anti-cancer potential of Hanmi p53 mRNA was demonstrated in a large number of cancers with p53 mutations, sparing to normal cells. Notably, p53 null/nonsense mutations were more sensitive to the Hanmi p53 mRNA compared to missense mutations or p53 WT cancer demonstrating a positive biomarker. High-throughput screening was performed to investigate the combination of Hanmi p53 mRNA with standard-of-cares, assessing the synergistic growth inhibition in cancer cells including lung, pancreatic, and breast, which exhibit high frequencies of p53 mutations. Taxanes such as paclitaxel, abraxane or docetaxel exhibited the best combinational synergy with Hanmi p53 mRNA in various p53-mutated cancer cell lines. Specifically, combination of Hanmi p53 mRNA and abraxane led to a dramatic increase in acetylated as well as phosphorylated p53 levels compared to Hanmi p53 mRNA alone. These results suggest that abraxane stabilizes wild-type p53 through acetylation, sustaining its expression and enhancing transcriptional activity in p53-mutated cancer. Restoration of p53 function highly elevated p21 expression, inducing G1 phase cell cycle arrest. Importantly, the combination of Hanmi p53 mRNA and abraxane synergistically amplified apoptotic activity, as evidenced by a marked increase in PARP cleavage. In vivo efficacy assessments of IV administration for LNP-encapsulated Hanmi p53 mRNA in combination with abraxane were conducted in PTX-preferred indication such as lung and ovarian cancer xenograft models. Tumor regression in mice treated with Hanmi p53 mRNA and abraxane was remarkably enhanced, with complete responses observed in 4 out of 5 mice, demonstrating the synergistic efficacy of the combination therapy. NGS-based gene set enrichment analysis conducted on NCI-H1373 xenograft tumors treated with p53-mRNA plus abraxane exhibited up-regulation of apoptotic gene sets compared to vehicle, consistent with our in vitro results. These results highlight Hanmi p53 mRNA exhibits strong synergy with taxanes, providing robust anti-cancer effects in indications requiring such therapeutic approaches. Citation Format: Jooyun Byun, Jongmin Hong, Seungheon Baek, Gunwoo Lee, Hocheol Shin, Miyoung Lee, Seung-Hyun Shin, Yong Ho Heo, Daejin Kim, In Young Choi. Hanmi’s p53 mRNA and abraxane synergistically promote tumor control in PTX-prefered cancer through p53 stabilization [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 5696.