Griffin, Patrick

Abstract The prognosis for patients afflicted with GBM has remained dismal in spite of decades of investigations, which speaks to the need to identify targets that drive essential functions in GBM, using well-tolerated, brain permeant inhibitors. Here we report our studies of MT-125, a small molecule inhibitor of non-muscle myosin IIA and IIB. 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 induces DNA damage and ferroptosis; and these effects explain why this drug synergizes with radiotherapy in prolonging survival in murine GBM models. MT-125 also induces oncogene addiction to receptor tyrosine kinase (RTK) signaling through a mechanism that is also driven by redox stress, and it also synergizes with FDA-approved RTK and MAP Kinase pathway inhibitors in vitro. Furthermore, MT-125 also synergizes with an FDA approved, RTK inhibitor in vivo, with the combination producing long-term, tumor free survival in an aggressive, preclinical murine model of GBM. MT-125’s long-term administration is well-tolerated at doses well above what is predicted to be therapeutic in multiple mammalian species. These data provide a powerful rationale for the clinical development of NMII targeting therapeutics to treat cancer and demonstrates that MT-125 has strong clinical potential for the treatment of GBM.