MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma.

in Cell by Rajappa S Kenchappa, Laszlo Radnai, Erica J Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K H Nagaiah, Gavin Rumbaugh, Michael D Cameron, Theodore M Kamenecka, Patrick R Griffin, Courtney A Miller, Steven S Rosenfeld

TLDR

  • Researchers discovered a small-molecule inhibitor, MT-125, that effectively treats glioblastoma by blocking tumor invasion and induction of DNA damage, and combines well with other therapies.
  • MT-125 demonstrates promising clinical potential as a first-in-class therapeutic for GBM treatment, leading to improved patient outcomes and potentially changing the landscape of GBM treatment.

Abstract

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.

Overview

  • The study focuses on MT-125, a small-molecule inhibitor of non-muscle myosin II, as a potential therapeutic for glioblastoma (GBM).
  • The study investigates the safety profile, brain penetrance, and effectiveness of MT-125 in murine GBM models.
  • The primary objective of the study is to evaluate the potential of MT-125 as a treatment for GBM, exploring its ability to block invasion, induce redox stress, and synergize with radiotherapy and other therapeutic agents.

Comparative Analysis & Findings

  • MT-125 has high brain penetrance and an excellent safety profile, making it a promising therapeutic agent for GBM.
  • MT-125 blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models, demonstrating its efficacy in reducing tumor growth and progression.
  • Combining MT-125 with FDA-approved PDGFR and mTOR inhibitors significantly improves survival in orthotopic GBM models, highlighting its potential for combined therapy.

Implications and Future Directions

  • The study's findings demonstrate the clinical potential of MT-125 as a first-in-class therapeutic for GBM treatment, offering a new approach for combining therapies to improve patient outcomes.
  • Future research directions may include evaluating the efficacy and safety of MT-125 in human clinical trials and exploring its potential as a maintenance therapy or as part of a targeted chemotherapy regimen.
  • Understanding the mechanisms by which MT-125 induces oncogene addiction to PDGFR signaling and its synergistic effects with radiotherapy and other agents may provide valuable insights for optimizing its use in GBM treatment.
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