Jan. 26, 2024
Mayo Clinic researchers have developed a therapeutic regime with a nearly 50% cure rate for laboratory models with glioblastoma. The treatment, which combines a small molecule inhibitor with a drug already approved by the Food and Drug Administration (FDA), is well tolerated by the laboratory models.
"The preliminary data is very compelling," says Steven S. Rosenfeld, M.D., Ph.D., a neuro-oncologist at Mayo Clinic in Jacksonville, Florida. "We've never seen these results with a small molecule inhibitor in this particular malignant model."
Progress in treating glioblastoma, the most common and lethal of primary brain tumors, has lagged developments in other cancers. Mayo Clinic is committed to finding novel therapeutics — an effort that requires dogged investigation of every promising lead.
"When a glioblastoma drug trial fails, people tend to just move on to the next hot candidate. We try instead to find out why the trial failed and what we can learn from that," Dr. Rosenfeld says.
Overcoming assumptions
Glioblastoma treatment poses particular challenges. Drugs must penetrate the blood-brain barrier, avoid efflux from the brain and cope with glioblastoma's heterogeneity.
"Every glioblastoma tumor consists of mixtures of multiple different cellular subpopulations," Dr. Rosenfeld says. "If the drug you're using kills one population, that's great. But the other three or four might continue to grow."
Dr. Rosenfeld's laboratory team focuses on approaches that target molecular motors, including nonmuscle myosin II. "It's a very versatile motor," Dr. Rosenfeld says. "It drives tumor invasion and is also involved in cell division and metabolic regulation."
"Novel approaches, guided by the unique biology of glioblastoma, are desperately needed to make an impact on this disease."
As described in 2019 in the Proceedings of the National Academy of Sciences, Dr. Rosenfeld's team discovered that myosin IIA, one member of the myosin II family of molecular motors, plays a major role in regulating tumor-related signaling. Myosin II also is involved in the production of reactive oxygen species, which contributes to the efficacy of radiation therapy — one of the standard therapies for glioblastoma.
"All of this makes myosin II seem like a very interesting target for a drug," Dr. Rosenfeld says. "But there's been an assumption that because all cells express myosin II, any drug that inhibited it would be toxic."
Nevertheless, the Mayo Clinic researchers began collaborating with scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, who had developed a myosin II inhibitor. Initial tests found that the inhibitor increased the survival of glioblastoma laboratory models by 40% to 50%. The therapy also was well tolerated.
"That was a great surprise," Dr. Rosenfeld says. "We saw no weight loss or behavioral changes, and blood studies were relatively unaffected."
The researchers then tested a combination of the myosin II inhibitor and the FDA-approved inhibitor in the highly malignant glioblastoma models. "We subsequently found that the drug combination is particularly effective when combined with radiation therapy," Dr. Rosenfeld says.
Thwarting glioblastoma cell resistance
Another avenue of research involves the development of small molecule inhibitors of mitotic kinesins. Although devoid of neurotoxicity, mitotic kinesin inhibitors haven't proved efficacious against glioblastoma, likely due to the development of drug resistance.
The Mayo Clinic researchers discovered a possible solution. In a study published in June 2022 in Cell Reports, the researchers showed that the development of this resistance occurs by a mechanism not previously described.
"We found that glioblastoma cells become resistant to this inhibitor in a very specific way, which can be targeted with FDA-approved drugs," Dr. Rosenfeld says. "We showed that we can double or triple the survival of animal models of glioblastoma simply by adding nontoxic doses of a second drug to make the first drug work better." Subsequent work found that the mechanism of resistance also applies to Aurora kinase inhibitors.
As a center of research excellence, Mayo Clinic is committed to translating laboratory results into patient care.
"Bridging that gap — getting a drug developed in the laboratory into the approval process and into the clinic — isn't a trivial endeavor," Dr. Rosenfeld says. "Our goal is eventually to introduce novel therapeutics into clinical trials. Novel approaches, guided by the unique biology of glioblastoma, are desperately needed to make an impact on this disease."
For more information
Picariello HS, et al. Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner. Proceedings of the National Academy of Sciences of the United States of America. 2019;116:15550.
Kenchappa RS, et al. Activation of STAT3 through combined SRC and EGFR signaling drives resistance to mitotic kinesin inhibitor in glioblastoma. Cell Reports. 2022;39:110991.
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