Journal Article

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma

Bota, Daniela A., Fowler, Christie D., Das, Bhaskar, Motahari, Zahra, Magge, Suresh N., Lepe, Javier J., Bautista, Malia R., Plant-Fox, Ashley S., Hoerig, Clay

2024

Overview

Medulloblastoma is the most common malignant brain tumor in children. It has WNT-driven, SHH-driven/ TP53 mutant, SHH-driven/ TP53 wildtype, and non-WNT/non-SHH subgroups. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encodes a mitochondrial import inner membrane translocase subunit and is responsible for the translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma. Methods: DAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo . Results: BT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p<0.0001; D425, 24 hours p = 0.0001, 48 hours p = 0.02). In DAOY cells, 3 μM BT9 delayed migration and significantly reduced DAOY and D425 cell invasion (p < 0.0001). It also modified mitochondrial respiratory function in both medulloblastoma cell lines. Compared to control, however, BT9 administration did not improve survival in a D425 orthotopic xenograft mouse model. Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antitumor activity / Apoptosis / Apoptosis - drug effects / Assaying / Brain cancer / Brain tumors / Care and treatment / Catheters / Cell culture / Cell death / Cell Line, Tumor / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Cerebellar Neoplasms - drug therapy / Cerebellar Neoplasms - metabolism / Cerebellar Neoplasms - pathology / Chemotherapy / Child / Children / Colony-stimulating factor / Diagnosis / Diseases / Drug resistance / Effectiveness / Electron transport / Experiments / Glioblastoma / Glioma / Granulocyte-macrophage colony stimulating factor / Humans / Laboratories / Leukocyte migration / Medulloblastoma / Medulloblastoma - drug therapy / Medulloblastoma - metabolism / Medulloblastoma - pathology / Membranes / Metabolism / Mice / Mitochondria / Mutants / Oxidative phosphorylation / p53 Protein / Pediatrics / Phosphorylation / Polyethylene terephthalate / Proteins / Respiration / Respiratory function / Subgroups / Translocase / Translocation / Veins & arteries / Wnt protein / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation