PP2A activation overcomes leptomeningeal dissemination in group 3 medulloblastoma

Sep 21, 2026

Leptomeningeal dissemination (LMD) is a principal cause of treatment failure in children with group 3 medulloblastoma. Building on prior findings on protein phosphatase 2A (PP2A) activation, this study evaluates preclinical and molecular effects of four novel PP2A activators (ATUX-6156, ATUX-6954, ATUX-1215, ATUX-5800). Treatment suppresses CIP2A, increases PP2A phosphatase activity, reduces viability, migration, and invasion, and modulates signaling to impair LMD initiation, dispersal, and colonization, including apoptosis via caspase 9/PARP signaling. In an intraventricular murine model, ATUX-1215 or ATUX-5800 prevents LMD, potentially via disruption of the CCL2-CCR2 axis through altered NF-κB phosphorylation via AKT signaling, supporting PP2A-based reactivation therapy.

LanguageEnglish

CategoryResearch & Report

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Pages14

Reading Time35 min

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Results

Novel PP2A activators as experimental therapeutics

PP2A activation and medulloblastoma leptomeningeal spread

RESEARCH ARTICLE PP2A activation overcomes leptomeningeal dissemination in group 3 medulloblastoma Received for publication, March 27, 2024, and in revised form, October 1, 2024 Published, Papers in Press, October 16, 2024, [https://doi.org/10.1016/j.jbc.2024.107892](https://doi.org/10.1016/j.jbc.2024.107892) Nazia Nazam 1,‡, Michael H. Erwin 1,‡, Janet R. Julson 1, Colin H. Quinn 1, Andee M. Beierle2, Laura V. Bownes 1, Jerry E. Stewart 1, Kyung-Don Kang3, Swatika Butey 1, Elizabeth Mroczek-Musulman4, Michael Ohlmeyer5, and Elizabeth A. Beierle 1, * From the 1Division of Pediatric Surgery, Department of Surgery, 2Department of Radiation Oncology, 3Division of Hematology Oncology, Department of Pediatrics, and 4Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA; 5Atux-Iskay, LLC, Plainsboro, New Jersey, USA Reviewed by members of the JBC Editorial Board. Edited by Paul Shapiro Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present preclinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in group 3 MB. The PP2A activators used in this study are ATUX-6156 and ATUX- 6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides). Treatment with these compounds led to suppression of the endogenous PP2A inhibitor, cancerous inhibitor of PP2A (CIP2A), enhanced phosphatase activity (10–60%), and reduced MB viability, migration, and invasion, prerequisites for MB cells to access the cerebrospinal ﬂuid, affecting the initiation stage of LMD. PP2A activator treatment of MB cells led to apoptosis mediated via caspase 9/PARP signaling due to decreased phosphorylation of Bad, impeding the dispersal stage of LMD. Cell proliferation and LMD-driving cellular traits and molecules pertinent to the third stage, colonization, were also affected. Treatment with ATUX-1215 or ATUX-5800 prevented LMD in an intraventricular murine model of MB, possibly mediated by disruption of the CCL2-CCR2 axis by altered NF-kB phosphorylation via disrupted AKT signaling. The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the ﬁrst indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneﬁcial as therapeutics for MB. Medulloblastoma (MB), a malignancy developing in the cerebellum, is the most common solid tumor afﬂicting the pediatric population, and the second most common pediatric malignancy surpassed only by leukemia (1) . Based on differences in genomic features and clinical behavior, MB is classiﬁed into four major molecular subtypes including WNT, ‡ These authors contributed equally to this work. * For correspondence: Elizabeth A. Beierle, elizabeth. beierle@childrensal. org. Sonic Hedgehog, group 3, and group 4 (2, 3). Group 3 MBs account for approximately 25 to 30% of all MB diagnoses, but bear the worst prognosis (2, 4), with 5-year overall survival (OS) just slightly higher than 50%, compared to 70% for the other 3 subtypes (4, 5). One of the major contributors to this poor outcome is leptomeningeal dissemination (LMD), the predominant pattern of metastasis involving tumor spread to the leptomeninges of the brain and spinal cord (6) . LMD remains an understudied domain of MB research. Consequently, novel therapeutic strategies designed to target LMD and effectively treat this devastating malignancy are warranted. Serine/threonine protein phosphatase 2A (PP2A) holoenzyme dephosphorylates an array of substrates that mediate a multitude of cell signaling pathways. PP2A is suggested to be a tumor suppressor across

FAQs

What problem does the study target in group 3 medulloblastoma?

It targets leptomeningeal dissemination (LMD), which is identified as a primary cause of treatment failure in group 3 medulloblastoma.

Which PP2A activators were tested, and what biological effects were observed?

The study tested ATUX-6156, ATUX-6954, ATUX-1215, and ATUX-5800. They suppressed CIP2A, enhanced PP2A phosphatase activity, and reduced medulloblastoma viability, migration, and invasion.

How do the PP2A activators affect LMD progression stages?

PP2A activation impacts LMD initiation by reducing prerequisites for access to cerebrospinal fluid, impairs dispersal by promoting apoptosis mediated by caspase 9/PARP signaling, and also alters cellular traits relevant to colonization.

Sep 21, 2026

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