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.

‘Sticky’ Particles Promise More Precise Drug Delivery for Brain Cancer

A Yale research team has found that by tinkering with the surface properties of drug-loaded nanoparticles, they can potentially direct these particles to specific cells in the brain.

By making nanoparticles bioadhesive, or “sticky,” the researchers have answered a long-standing question: Once you get the particles to the brain, how do you get them to interact with the cancer cells there? Their findings are published May 19 in Nature Communications.

“Until now, research has focused on whether you can load the nanoparticles with drugs and whether we can get them into the brain at all, without thinking too much about what cells they go to,” said senior author W. Mark Saltzman, the Goizueta Foundation Professor of Chemical and Biomedical Engineering, professor of cellular and molecular physiology, and member of the Yale Cancer Center. “This is the first exploration of the particles’ affinity for different cells.”

The ability for nanoparticles to deliver drugs to specific areas of the body holds great promise for fighting cancer and other diseases while minimizing the side effects of drugs that are often very toxic, according to scientists. Their use in treating brain cancer, though, has been particularly challenging. That’s partly due to the blood-brain barrier, which acts to keep foreign elements out of the brain. Researchers have been able to get nanoparticles to penetrate the brain in recent years with help from a polymer coating that gives the particles “stealth” properties, allowing the particles to hide from the body’s immune system. Those same stealth properties, however, also keep cells from recognizing the particles.

“So they’re just kind of in the space between the cells, and not really doing what they’re supposed to be doing,” said co-lead author Eric Song, a graduate student at the Yale School of Medicine.

The Yale researchers found that they could correct for this by altering the chemistry of the nanoparticles. In two groups of rats — ones with brain tumors and ones with healthy brains — the researchers found that differences in the particles’ surface chemistry played a significant role in whether the particles were internalized by cells in the brain.

They covered one group of particles with polymers rich in aldehydes, which chemically bind to amines — a compound found in most proteins. These bioadhesive particles were most likely to be taken up by cells of all types in the brain: Tumor cells were among those that internalized the bioadhesive particles at a particularly high rate.

These results suggest that tailoring the chemical properties of particles provides an opportunity to control the distribution of the drugs they’re carrying, said the researchers. Further, they believe that the particles could be tailored for specific therapies to improve efficacy in target cells, and minimize toxicity to the cells they’re not targeting.