If you’ve been reading up on brain cancer since hearing of Senator John McCain’s recent diagnosis, you may already know that his type of cancer, glioblastoma, has a fairly grim outlook. Fewer than 5% of those diagnosed with glioblastoma survive to five years, and this cancer claims half its victims within 15 months.
Given the rapid advances in cancer care over the past decade or so—including some truly remarkable strides in completely flipping the survival odds of some cancers—glioblastoma remains a stubborn holdout, as I've written about at Cure magazine. No new therapy has emerged in decades that can do any more than the current standard of care. So what makes this cancer so incredibly difficult to treat?
Unfortunately, it’s multiple problems—starting with the obvious: “These tumors are in the brain, and that’s such a delicate and difficult environment,” said Tom Curran, Ph.D., past president of the American Association for Cancer Research. “If you have a cancer on your little finger, you can take off the finger and still have a good quality of life,” Curran said. “You can’t have a quality of life without your brain.”
In nearly every other part of the body, there’s enough real estate that cutting wide and deep to remove a tumor still usually leaves enough tissue for someone to live a relatively normal life once the cancer is gone. Not so with the brain.
“With the brain, you can’t cut deep because the deeper you cut, the more side effects you’re causing, the more damage you’re causing," said Curran, also executive director of the Children’s Research Institute and the Donald J. Hall Eminent Scholar in Pediatric Research at Children’s Mercy in Kansas City.
The brain isn’t very big, and nearly every piece of it matters.
“The brain is who we are,” said Eric Holland, M.D., Ph.D., director of the Human Biology Division and senior vice president at Fred Hutchinson Cancer Research Center in Seattle. “All of the rest of us are just connected to it.”
It’s not just physically cutting out a tumor that can have devastating consequences, either. Therapies such as chemotherapy or even targeted therapy run the risk of damaging the brain, too, Curran explained.
“We need to find ways of identifying and eliminating brain tumors without damaging the surrounding brain tissues, which is essential for lots of different functions,” Curran said.
And so far, researchers haven’t found a way to do that.
One reason is the way the tumor grows. Even if surgeons could cut wide and deep, it would be nearly impossible to scrape out every last cancer cell because glioblastoma is an aggressive cancer that spreads rapidly in every direction.
“The cancer cells diffusely invade the brain—they wander all over the place like ants in the grass,” Holland said. “They’re recapitulating the behavior of cells during normal development."
So the only way to ensure all of a tumor is gone is to remove every place it could have spread—except, again: “You can’t cut someone’s head off and call that a cure,” said Holland, also director of the Brain Tumor Center at the University of Washington.
So once a neurosurgeon has removed as much of the tumor as possible, they have to figure out how to go after the cancer cells that were inevitably left behind. That’s where another obstacle comes in.
Because the brain’s function is so important, it's protected from substances otherwise traveling freely throughout the body. A thin membrane surrounding the brain called the blood-brain barrier keeps out toxins while only letting in certain molecules, or some small enough to penetrate it. Think of the blood-brain barrier as millions of bouncers who are really picky about who gets into the club. And once you’re in? No fighting—there's almost no immune system presence.
“The brain is an immuno-privileged site,” Holland explained. “It contains very few T-cells,” the immune cells that destroy foreign molecules and instruct other immune cells on what to attack. An immune reaction—fighting a pathogen or other foreign body—causes inflammation, and the brain can’t really afford any inflammation when it's the command center for the rest of the body. So when something pathogenic invades, the brain has few defenses on the inside to fight back.
Oncologists therefore need treatments that can get past the blood-brain barrier and then kill all the tumor cells. But enter the next problem: glioblastoma is never a single, monolithic mass.
“The salient feature of glioblastoma is the diversity of the cell populations across different patients and within a single patient,” Curran explained.
In other words, the genetic makeup of its cells differ from one to the next, often dramatically. With many cancers, oncologists try to identify a specific mutation or other target present in all the cancer cells so they can tailor a drug to go after that target, thereby destroying all the cancer cells. But that only works if all the cells have that target.
“You can’t target a single thing if there’s not a single thing,” Holland said. “There’s just such heterogeneity in these tumors that they’re always going to find a way around” whatever doctors throw at them. Even if doctors could find such a drug for one patient, that doesn't help the next patient whose tumor is just as diverse.
This extreme heterogeneity is not unique to glioblastoma, but it is “particularly striking,” explained Holland. Cells contain chunks of DNA floating around outside their chromosomes, and these chunks aren’t evenly distributed across all the cells.
“Each cell is like dealer’s choice in what pieces of DNA they get,” Holland said. “If some of these DNA pieces give a cell a gross advantage, it puts selective advantage on that cell and potentially spreads.”
So a targeted therapy that wipes out 80% of a tumor’s cells may seem great until the other 20% flourish. That’s why the current standard of care centers on radiation and chemotherapy, both indiscriminate destroyers.
“What you can do is generalized damage,” Holland said. “Chemotherapy and radiation work relatively well—but not great—because they break the DNA in all the cells.”
Still, they don’t kill all the tumor cells, which continue diversifying.
“We have to treat the tumors with the available therapies even if they don’t work very well in case they can help,” Curran said. “If they fail, as they invariably do with glioblastoma, then we can move on to the more novel, unproven therapies, but by then the tumor has gained even more variability. That’s why glioblastoma has evaded both research and novel therapeutic interventions, because it’s like the hydra. You chop off one head, and two more grow.”
Hercules defeated the hydra by using more than one weapon, so researchers are looking for what combinations of therapies might work to defeat glioblastoma. That has led to hundreds of possible drugs in hundreds of clinical trials, though few stand out with much success yet. In the next post here, I’ll discuss what this crowded field of experimental therapies looks like and how researchers categorize them.
