Generating Synthetic Lethality in Glioblastoma with a First-In-Class Non-Muscle Myosin II Inhibitor

PROJECT SUMMARY/ABSTRACT We have shown that in addition to being irreplaceable for glioblastoma (GBM) invasion and mitosis, members of the non-muscle myosin II (NMII) family of molecular motors also regulate oncogenic signaling, mitochondrial homeostasis, and reactive oxygen formation. This suggests that targeting the two predominant NMII isoforms in GBM (NMIIA and IIB) will synergize with signal transduction inhibitors and with therapies that depend on reactive oxygen, including radiation. We find that MT-125, a non-toxic, CNS permeant small molecule inhibitor of NMIIA and NMIIB prolongs median survival by ~30% as a single agent. Furthermore, when it is combined with sunitinib, a multi-RTK inhibitor, MT-125 prolongs median survival nearly 2-fold over vehicle and produces long term, tumor-free remissions in nearly half of mice. In addition, MT-125 sensitizes GBMs to radiotherapy. Our central hypothesis is that by uncovering the mechanisms for these remarkable forms of synergy between MT-125, signaling inhibitors, and radiation therapy, we can optimize the use of this highly novel therapeutic in studies that should lay the groundwork for first-in-human clinical trials.