Abstract 4223: Mouse clinical trials (MCT) and other comprehensive pharmacology approaches highlight protein arginine methyltransferase 1 (PRMT1) targeting in various solid tumors with promising efficacy and combined mode-of-actions (MoAs) beyond epi

Abstract Arginine methylation is the most abundant post-translational modifications which provide docking site for protein binding and interaction (e.g. with the aromatic cage of the Tudor domain proteins), triggering a series of downstream epigenetic regulation and cellular functions or processes. PRMT1 is the major type-I PRMTs responsive for monomethylation and asymmetric dimethylation of arginines in histone tails or non-histone protein substrates. Highly expressed in various lineages of cancers with poor survival such as non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma (PAAD), triple-negative breast cancer (TNBC), esophageal squamous cell carcinoma (ESCC), gastric cancer (GA), PRMT1 has been extensively reported for targeting in cancer with profound and broad tumor-intrinsic/extrinsic modulation to repress cancer growth, metastasis or refractory immunity. Here we showed that CTS2190, the only clinically active investigational drug of PRMT1 currently in phase I/II study (NCT06224387), could drive cancer specific mode-of-actions combining epigenetic gene expression, DNA damage response (DDR), cell cycle arrest, signal transduction and immunity activation. We applied an innovative, well-designed, patient-derived xenograft (PDX)-based mouse clinical trial (MCT) approach to evaluate CTS2190 efficacy in an all-comer solid patient panel. CTS2190 demonstrated excellent tumor growth inhibition and regression in GA, NSCLC, PAAD, ESCC, etc. We also explored and validated the efficacy and proposed MoAs of CTS2190 in multiple cellular or in vivo pharmacology approaches as well as the synergistic effects of CTS2190 in a couple of MoA-driven and biomarker-guiding combinatorial approaches with chemo-, targeted-, radio- and/or immune-therapies. These results indicate the comprehensive anti-cancer mechanisms of CTS2190 in targeting PRMT1. CTS2190 not only demonstrates synthetic lethality with epigenetic instability, DDR, or RNA splicing (RS) dysregulation, but also as an ideal partner for a wide range of cancer therapies, including combinations with PRMT5i, a type-II PRMT member in both MTAPnull and wild-type genetic context. Ongoing clinical and translational studies for CTS2190 will pioneer the breakthrough and pave the way for developing more next-generation epigenetic therapies in solid tumors. Citation Format: Hui Shi, Xingnian Fu, Yilin Liu, Qiugeng Ouyang, Jiaxin Huang, Long Wang, Shuning Xing, Youzhen Wang, Yuan Mi, Haiping Wu. Mouse clinical trials (MCT) and other comprehensive pharmacology approaches highlight protein arginine methyltransferase 1 (PRMT1) targeting in various solid tumors with promising efficacy and combined mode-of-actions (MoAs) beyond epigenetic regulation [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 4223.