Abstract B037: RVU305, a brain-penetrant MTA-cooperative PRMT5 inhibitor, shows efficacy in GBM preclinical models

Abstract Gliomas, the most common type of primary brain malignancy, represent a significant clinical challenge due to their complexity, heterogeneity and often poor prognosis. High-grade gliomas, such as glioblastoma multiforme (GBM), are particularly aggressive and resistant to conventional therapies. Despite advances in surgical techniques, radiotherapy, and chemotherapy, the prognosis for patients with high-grade gliomas remains dismal, with median survival rarely exceeding 15 months. The infiltrative nature of these tumors, their molecular diversity, and the protective role of the blood-brain barrier contribute to the limited efficacy of current treatment modalities. As such, high-grade gliomas continue to represent a major unmet medical need, underscoring the urgency for developing novel therapies. Homozygous deletions of methylthioadenosine phosphorylase (MTAP), located on chromosome 9p21, are observed in 10 to 15% of all human tumors, with up to 50% of GBM cases exhibiting MTAP loss. This deletion leads to a substantial methylthioadenosine (MTA) build-up within cells. At high concentrations, MTA acts as a highly selective inhibitor of the PRMT5 methyltransferase, specifically competing with its substrate, S-adenosylmethionine (SAM). Hence, selectively targeting residual PRMT5 levels, which are essential for survival of cancers, represents a promising strategy for eliminating cancer cells with homozygous MTAP deletion. RVU305 is a preclinical-stage, small molecule MTA-cooperative PRMT5 inhibitor that selectively targets PRMT5 activity in MTAP-deficient cells by exploiting a synthetic lethal interaction. RVU305 demonstrated in vivo brain penetration in preclinical models including cynomolgus monkey, indicating that RVU305 has the potential to address the critical unmet medical need in GBM treatment. This novel compound exhibited robust antiproliferative activity selectively in MTAP-deleted cell lines, including multiple CNS-derived models. In vitro studies demonstrated a dose-dependent reduction in symmetric dimethylarginine (SDMA)-modified protein levels, indicative of PRMT5 inhibition. RVU305 was evaluated across a range of GBM cell lines, including those with MTAP deletion (U87MG, U118MG, LN18) and MTAP wild-type (U251MG, LN229), demonstrating pronounced efficacy specifically in the MTAP-deleted group. This differential response became more pronounced following a prolonged 10-day treatment. In vivo, RVU305 displayed signs of antitumor activity in an orthotopic U87MG GBM mouse model. Taken together, these studies confirm that RVU305 is a potent, brain-penetrant MTA-cooperative PRMT5 inhibitor which induces a strong synthetic lethal phenotype in MTAP-deleted cancers, including GBM, offering an exciting therapeutic opportunity for a large patient population and potentially addressing an unmet clinical need. Citation Format: Anna Bartosik, Agnieszka Szymula, Kinga Michalik, Aniela Gołas, Kamil Kuś, Justyna Martyka, Magdalena Bońkowska, Marta Obacz, Lea Hirsl, Paulina Podkalicka, Jacek Faber, Adam Radzimierski, Aneta Bobowska, Aleksandra Więckowska, Agata Stachowicz-Wałaszek, Agnieszka Ludwig-Słomczyńska, Diego Coelho, Kamila Kozłowska-Tomczyk, Szymon Woroszyło, Gary Wilkinson, Andrew Thomason1, Hendrik Nogai, Krzysztof Brzózka, Milena Mazan. RVU305, a brain-penetrant MTA-cooperative PRMT5 inhibitor, shows efficacy in GBM preclinical models [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 B037.