Each year, about 14,000 people in the United States are diagnosed with glioblastoma, one of the deadliest primary brain tumors. With standard treatments of surgery, radiation, and chemotherapy offering a median survival of 14–16 months—and approximately half of patients harboring tumors resistant to approved drugs—novel therapeutic approaches are urgently needed.
In a study published in Cell titled “MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma,” researchers from the Wertheim UF Scripps Institute, Mayo Clinic, and collaborators report a promising strategy. Their investigational compound, MT-125, directly targets non-muscle myosin II, a molecular “motor” critical for glioblastoma invasion and cytokinesis. Remarkably, MT-125 appears to render previously resistant tumors newly sensitive to both radiation and kinase inhibitors, while blocking the cancer’s ability to invade brain tissue.
“We know glioblastoma patients are awaiting a breakthrough, and we’re moving as fast as humanly possible,” said senior author Courtney Miller, PhD, of the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology. The team’s approach stands out by targeting non-muscle myosin IIA and IIB (NMIIA/IIB)—key players downstream of many converging cancer signaling pathways. While oncogenic kinase inhibitors have generally failed in glioblastoma, likely due to pathway redundancies, NMII sits at a convergence point that makes it a hopeful target.
MT-125, a blebbistatin derivative, potently inhibits NMIIA/IIB with minimal impact on cardiac myosin. In mouse models, the researchers reported that the drug showed excellent brain penetrance, a strong safety profile, and did not affect cardiac function or cause significant toxicities at doses well above what is predicted to be therapeutic.
Mechanistically, MT-125 disrupts mitochondrial fission, leading to elevated reactive oxygen species (ROS), DNA damage, and ferroptosis, a type of iron-dependent cell death. It also triggers “oncogene addiction,” causing glioblastoma cells to ramp up PDGFR and mTOR signaling to survive the stress. The upside is that this may make tumors exquisitely vulnerable to existing kinase inhibitors like sunitinib or the PI3K/mTOR inhibitor paxalisib.
In preclinical models, combining MT-125 with sunitinib doubled survival compared to either drug alone, and yielded long-term remission in 40% of treated mice. Adding MT-125 also dramatically sensitized tumors to radiotherapy.
“We found in mice that combining MT-125 with a number of kinase inhibitors created long periods of a disease-free state that we haven’t seen in these mouse models before,” said Steven Rosenfeld, MD, PhD, a neuro-oncologist at Mayo Clinic and study co-lead. The FDA has granted permission to advance MT-125 into clinical trials.
Importantly, MT-125’s unique action could extend beyond glioblastoma. By exploiting cancer cells’ dependence on myosin-driven mechanics and ROS buffering, the strategy may hold promise for other difficult-to-treat malignant gliomas and other tumors.
Nonetheless, researchers caution that while MT-125 caused multinucleation and polyploidy—hallmarks of anti-proliferative stress—long-term implications of inducing chromosomal instability require careful follow-up. Still, the prospect of a first-in-class, brain-penetrant therapy that directly targets the biomechanical underpinnings of cancer cell survival marks an exciting frontier.
A related compound, MT-110, designed to curb methamphetamine cravings via similar myosin pathways, is also advancing toward clinical trials, underscoring the broad therapeutic reach of targeting cellular “motors.”
The post Myosin-Targeting Drug Sensitizes Glioblastoma to Treatment in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.
In a study published in Cell titled “MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma,” researchers from the Wertheim UF Scripps Institute, Mayo Clinic, and collaborators report a promising strategy. Their investigational compound, MT-125, directly targets non-muscle myosin II, a molecular “motor” critical for glioblastoma invasion and cytokinesis. Remarkably, MT-125 appears to render previously resistant tumors newly sensitive to both radiation and kinase inhibitors, while blocking the cancer’s ability to invade brain tissue.
“We know glioblastoma patients are awaiting a breakthrough, and we’re moving as fast as humanly possible,” said senior author Courtney Miller, PhD, of the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology. The team’s approach stands out by targeting non-muscle myosin IIA and IIB (NMIIA/IIB)—key players downstream of many converging cancer signaling pathways. While oncogenic kinase inhibitors have generally failed in glioblastoma, likely due to pathway redundancies, NMII sits at a convergence point that makes it a hopeful target.
MT-125, a blebbistatin derivative, potently inhibits NMIIA/IIB with minimal impact on cardiac myosin. In mouse models, the researchers reported that the drug showed excellent brain penetrance, a strong safety profile, and did not affect cardiac function or cause significant toxicities at doses well above what is predicted to be therapeutic.
Mechanistically, MT-125 disrupts mitochondrial fission, leading to elevated reactive oxygen species (ROS), DNA damage, and ferroptosis, a type of iron-dependent cell death. It also triggers “oncogene addiction,” causing glioblastoma cells to ramp up PDGFR and mTOR signaling to survive the stress. The upside is that this may make tumors exquisitely vulnerable to existing kinase inhibitors like sunitinib or the PI3K/mTOR inhibitor paxalisib.
In preclinical models, combining MT-125 with sunitinib doubled survival compared to either drug alone, and yielded long-term remission in 40% of treated mice. Adding MT-125 also dramatically sensitized tumors to radiotherapy.
“We found in mice that combining MT-125 with a number of kinase inhibitors created long periods of a disease-free state that we haven’t seen in these mouse models before,” said Steven Rosenfeld, MD, PhD, a neuro-oncologist at Mayo Clinic and study co-lead. The FDA has granted permission to advance MT-125 into clinical trials.
Importantly, MT-125’s unique action could extend beyond glioblastoma. By exploiting cancer cells’ dependence on myosin-driven mechanics and ROS buffering, the strategy may hold promise for other difficult-to-treat malignant gliomas and other tumors.
Nonetheless, researchers caution that while MT-125 caused multinucleation and polyploidy—hallmarks of anti-proliferative stress—long-term implications of inducing chromosomal instability require careful follow-up. Still, the prospect of a first-in-class, brain-penetrant therapy that directly targets the biomechanical underpinnings of cancer cell survival marks an exciting frontier.
A related compound, MT-110, designed to curb methamphetamine cravings via similar myosin pathways, is also advancing toward clinical trials, underscoring the broad therapeutic reach of targeting cellular “motors.”
The post Myosin-Targeting Drug Sensitizes Glioblastoma to Treatment in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.