Combination Treatment Targeting Glucose in Advanced Brain Cancer Shows Promising Results in Preclinical Study

UCLA scientists have discovered a potential combination treatment for glioblastoma, the deadliest form of brain cancer in adults. The three-year study led by Dr. David Nathanson, a member of UCLA’s Jonsson Comprehensive Cancer Center, found that the drug combination tested in mice disrupts and exploits glucose intake, essentially cutting off the tumor’s nutrients and energy supply. This treatment then stimulates cell death pathways—which control the cancer cells’ fate—and prevents the glioblastoma from getting bigger.

The combination treatment works by manipulating sugar metabolism with the FDA-approved drug erlotinib against one of the most common genetic alterations in glioblastoma, a cell surface protein known as EGFR. The researchers found that erlotinib treatment reduces sugar uptake in the majority of glioblastomas studied, thereby creating a metabolically vulnerable state for these brain tumors. The researchers then exploited this metabolic deficiency with an experimental drug called idasanutlin, which activates a protein called p53 to promote glioblastoma cell death and stimulate tumor regression in mice. Nathanson and his team also demonstrated that positron emission tomography, or PET, imaging can predict which tumors would respond best to this combination treatment.

BACKGROUND 

These findings build on previous research by Nathanson, who was a co-author of the initial study in 2013. That research showed that EGFR genetic alterations promote sugar uptake in glioblastomas. The researchers also found they could not directly attack sugar metabolism in the brain, due to potential side effects, since normal tissue requires sugar to survive.

Glioblastoma is one of the most lethal human cancers, with a median survival rate in adults of just 15 months after diagnosis.

METHOD

Researchers conducted the study using 19 human glioblastoma cells from different people. Some of the cells were implanted in the mice to analyze the effectiveness of the drug combination treatment. The researchers used PET imaging to predict which tumors would benefit from the drug combination.

The researchers also used an assay, or an assessment tool, developed by collaborators at Harvard University to measure how close a brain tumor cell is to the death threshold while targeting sugar metabolism.

IMPACT

The next stage of research will be to test the combination treatment on people with glioblastomas in clinical trials. Eventually, the researchers might design a new strategy involving the combination treatment that would attack and kill the glioblastoma altogether.

Drug Developed at University of Minnesota Increases Survival in Dogs with Cancer

A breakthrough trial at the University of Minnesota testing a new UMN-developed drug resulted in improved survival rates for dogs diagnosed with a cancer called hemangiosarcoma (HSA). The results were published today in the journal Molecular Cancer Therapeutics.

“This is likely the most significant advance in the treatment of canine HSA in the last three decades,” said study co-author Jaime Modiano, V.M.D., Ph.D. professor in the University of Minnesota College of Veterinary Medicine and member of the Masonic Cancer Center, University of Minnesota.

Canine HSA is a common, aggressive, incurable sarcoma. It is remarkably similar to angiosarcoma, which affects humans. Both cancers typically spread before diagnosis and the survival time for affected patients is extremely short, even with aggressive treatment. Only 50% of humans diagnosed with angiosarcoma live longer than 16 months and the prognosis for dogs with HSA is similarly dire: less than 50% will survive 4-6 months and only about 10% will be alive one-year after their diagnosis.

The study tested a drug called eBAT, invented by study senior author Daniel Vallera, Ph.D., professor at the University of Minnesota Medical School and Masonic Cancer Center.

“eBAT was created to specifically target tumors while causing minimal damage to the immune system. HSA is a vascular cancer, meaning it forms from blood vessels. eBAT was selected for this trial because it can simultaneously target the tumor and its vascular system,” said Vallera.

Traditional cancer treatments have side effects that can be very hard on patients. “In this trial we aimed for a sweet spot by identifying a dose of eBAT that was effective to treat the cancer, but caused no appreciable harm to the patient. Essentially we’re treating the cancer in a safer and more effective way, improving quality of life and providing a better chance at survival,” lead study author Antonella Borgatti, D.V.M., M.S., associate professor with the University of Minnesota College of Veterinary Medicine said.

eBAT was tested on 23 dogs of various breeds, both large and small, with HSA of the spleen. Dogs received three treatments of eBAT after surgery to remove the tumor and before conventional chemotherapy. The drug treatment improved the 6-month survival rate to approximately 70%. Furthermore, five of the 23 dogs that received eBAT treatment lived more than 450 days.

The positive results for canine patients, the similarities between this cancer and angiosarcoma in humans, and the fact that many other tumor types can be targeted by eBAT, make a strong case for translating this drug into clinical trials for human cancer patients. The researchers want these results to bring hope to those touched by this disease.

“This drug was invented here at the University of Minnesota, developed here, manufactured here, tested here and showed positive results here. We would also like this drug to achieve positive outcomes for humans here,” Modiano said.

“The ultimate goal for all of us is to create a world in which we no longer fear cancer,” Modiano said.

This project is an example of the remarkable progress that is being made through collaborations among the multiple colleges and schools within the University of Minnesota’s Academic Health Center.

Funding was provided by many sources, including various foundations and individuals along with the National Institutes of Health, showing the broad interest in identifying cures for these devastating cancers.