Southern Research oncology researcher Dr. Bo Xu, M.D., Ph.D., says new research suggests combining an experimental enzyme blocker and a standard chemotherapy drug could improve treatments for patients with glioblastoma, a deadly brain cancer.
The pairing of the enzyme inhibitor known as SLC-0111 and the chemo drug temozolomide is the focus of a research project led by Anita Hjelmeland, Ph.D., at the University of Alabama at Birmingham (UAB). Southern Research collaborated on the project.
A key finding is that adding SLC-0111 significantly improved the effectiveness of the chemo drug in experiments involving glioblastoma. In both cell culture and animal tests, the pairing delivered better results, as measured by regression of the tumor, than either the enzyme blocker or the chemo drug did on its own.
Glioblastoma multiform (GBM) is an aggressive brain cancer, and its cause is unknown. The median survival rate for patients being treated for glioblastoma is 14.6 months, with a low rate of survival beyond five years, according to the American Brain Tumor Association.
Treatment usually involves surgery, chemotherapy and radiation, but the cancer tends to recur months later.
“There are limited options today for glioblastoma patients,” said Xu, Distinguished Fellow and Chair of the Oncology Department at Southern Research. “There is an urgent need for new drugs for treating this disease.”
The UAB research project is targeting a carbonic anhydrase enzyme known as CA9, which GBM cells overexpress it to maintain balance in their microenvironment in the brain. Blocking the enzyme using SLC-0111 could disrupt that balance and allow the chemo drug to better do its work.
“Our experiments strongly suggest that a strategy to target a carbonic anhydrase that is increased in glioblastoma, CA9, will improve temozolomide efficacy,” Hjelmeland said in a UAB News story. “We believe the drug combination could improve patient outcomes in glioblastomas sensitive to chemotherapy.”
Southern Research’s role in the project was to help the UAB researchers better understand the possible reason the combination worked better against glioblastoma than they did individually, according to Joshua Fried, a UAB postgraduate student in cancer biology and a researcher in Xu’s lab.
The evidence pointed to the DNA damage response, a network of cellular pathways that takes action against constant threat posed by of damage to DNA in the body. Because breakdowns in this response can trigger cancer formation, hijacking the pathway has become the foundation of oncology therapies.
“We saw that there was an increase in the DNA damage response when the SLC-0111 and temozolomide were combined, and that the damage persisted longer than with either treatment alone,” Fried said. “It’s sort of a surprise because you wouldn’t think that something that regulates pH-balance like SC-0111 would contribute to the DNA damage response.”
Xu said the project illustrates the long-standing collaboration that exists between UAB and Southern Research on these types of projects. The two organizations are partners in the Alabama Drug Discovery Alliance, which has developed a pipeline of potential therapies for several debilitating diseases.
The study by Hjelmeland’s team was published in JCI Insight. Xu and Fried are listed as co-authors on the paper.