MT - 125抑制非肌肉肌球蛋白IIA和IIB，并延长胶质母细胞瘤患者的生存期。
MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma.
作者信息
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
机构信息
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.
出版信息
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。
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