Abstract B059: A small molecule activator of the tumor suppressor phosphatase PP2A overcomes leptomeningeal dissemination in group 3 medulloblastoma

Abstract Historically introduction of new cancer therapeutics in children has lagged adults by six to ten years. New treatment options for medulloblastoma, and other pediatric cancers, are urgently needed. Medulloblastoma is the most common primary brain tumor in the pediatric population. Once considered a singular pathology, medulloblastoma is now classified into four molecular subgroups: group 3 tumors account for approximately 25-30% of medulloblastomas and have the worst prognosis. Despite current multimodal therapy with surgery, chemotherapy and radiation, infants and children with Group 3 tumors have a 5-year overall survival of 45 and 58%, respectively. Furthermore, children who survive with current treatment regimens often suffer from long-term motor, sensory, endocrine, and neuropsychologic sequelae. These children are a patient population that requires novel therapies, applied alone or in combination with standard approaches, to effectively treat their disease and provide less toxic therapies with fewer long-term effects. We present data on a novel small molecule activator of the tumor suppressor phosphatase PP2A as a potential therapeutic for medulloblastoma. The lead compound, (-)-ATUX-1215 elicits a robust PP2A activating effect in cancer cells with dephosphorylation of direct PP2A targets such as pERK and pAKT which are key drivers of medulloblastoma tumor growth, and metastasis. PP2A activation is also correlated with suppression of the endogenous cellular inhibitors CIP2A and PME-1. We also observe negative regulation of PP2A targets such as anti-apoptotic p-Bcl2 which are key in conferring resistance to existing therapies. Leptomeningeal metastases are the most important cause of morbidity and mortality for group-3 medulloblastoma patients. We present data showing that ATUX-1215, suppresses leptomeningeal dissemination in a state-of-the-art PDX mouse model of group-3 medulloblastoma. Further our data suggest that ATUX-1215 will ameliorate unwanted pro-metastatic effects induced by first line radiation therapy by suppressing CCL2/CCR2 expression via NF-kB signaling. This is a key consideration introducing a new compound into pediatric patients. Data demonstrating significant synergy with CHK1 kinase inhibition is also presented.In vitro safety, drug metabolism, pharmacokinetic data are presented that demonstrate that ATUX-1215 is a viable drug candidate and warrants further evaluation in patients where leptomeningeal metastases is occurring after first line therapy. Citation Format: Nazia Nazam, Michael H. Erwin, Janet R. Julson, Kyung-Don Kang, Swatika Butey, Colin H. Quinn, Andee M. Beierle, Laura V. Bownes, Elizabeth Mroczek-Musulman, Muhammad Sheraz, Johanna A. Ohlmeyer, Brown L. Brown, Michael Ohlmeyer, Elizabeth A. Beierle. A small molecule activator of the tumor suppressor phosphatase PP2A overcomes leptomeningeal dissemination in group 3 medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B059.