Kenchappa Rajappa S, Radnai Laszlo, Young Erica J, Zarco Natanael, Lin Li, Dovas Athanassios, Meyer Christian T, Haddock Ashley, Hall Alice, Toth Katalin, Canoll Peter, Nagaiah Naveen K H, Rumbaugh Gavin, Cameron Michael D, Kamenecka Theodore M, Griffin Patrick R, Miller Courtney A, Rosenfeld Steven S
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA.
Department of Molecular Medicine, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
Cell. 2025 Jun 3. doi: 10.1016/j.cell.2025.05.019.
Glioblastoma (GBM) is the most lethal of primary brain tumors. Here, we report our studies of MT-125, a small-molecule inhibitor of non-muscle myosin II. MT-125 has high brain penetrance and an excellent safety profile, blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.
胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤。在此，我们报告了对MT - 125的研究，它是一种非肌肉肌球蛋白II的小分子抑制剂。MT - 125具有高脑渗透性和出色的安全性，可阻断GBM侵袭和胞质分裂，并延长小鼠GBM模型的生存期。通过损害线粒体分裂，MT - 125增加氧化还原应激及随之而来的DNA损伤，并与放疗产生协同作用。MT - 125还通过一种由氧化还原应激驱动的机制诱导癌基因对PDGFR信号传导产生依赖，并且在体外与FDA批准的PDGFR和mTOR抑制剂产生协同作用。与此一致的是，我们发现将MT - 125与PDGFR抑制剂舒尼替尼或磷脂酰肌醇3激酶（PI3K）/mTOR联合抑制剂帕唑帕利联合使用，在原位GBM模型中比单独使用任何一种药物都能显著提高生存期。我们的结果表明，MT - 125是一种具有强大临床治疗GBM潜力的首创疗法。
