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Sen. John McCain is expected to get the same glioblastoma treatment — surgery, chemotherapy and radiation — as his late friend Sen. Ted Kennedy received nine years ago. And the prognosis remains nearly as grim: Most patients live less than 18 months past their diagnosis.
But those stats mask tremendous progress in basic research, and oncologists say they are more optimistic than they’ve ever been that a major treatment advance is coming.
“I tell patients all the time to stay hopeful,” said Dr. Alexandra Golby, director of Image-Guided Neurosurgery at Brigham and Women’s Hospital in Boston. “One day we're going to have a breakthrough. Other diseases have had huge breakthroughs. So I tell patients: You have to stay positive.”
When Dr. Jay Loeffler, chief of radiation oncology at Massachusetts General Hospital, entered the field 30 years ago, there were just a handful of scientists interested in glioblastoma, he said.
Now, it’s one of the most popular areas of research, he said, because young scientists see the potential for making their mark. Such a heightened level of interest is sure to lead to advances within the next five years, Loeffler said.
There is also a tiny minority of patients who are now surviving for years with glioblastoma. Those successes suggest that there is a path forward — if doctors can find it, he said.
Glioblastoma lags behind other cancers in terms of treatment advances because the brain is dangerous to operate on and difficult to reach with drugs, and because the tumor itself is so unusual, several specialists said.
Unlike the lump we think of with, say, breast cancer, glioblastoma has tendrils — or skinny fingers — that stretch outward from the visible tumor, according to Dr. William Curry, director of neurosurgical oncology at Massachusetts General Hospital.
“It's really a network of cells that infiltrate across and through normal brain tissue even at the time that we make that initial diagnosis,” he said.
Surgeons have managed to extend glioblastoma patients' lives by cutting out more and more of their initial tumor. But a knife can never cure the disease because of these remaining tendrils, which are invisible on scans and during surgery, Curry said.
Radiation has the same problem. It has been getting better at targeting cells that doctors can see, but it always misses some.
About a decade ago, a new form of chemotherapy offered a significant treatment advance. But glioblastoma is loaded with mutations that allow some cells to survive the chemical onslaught. And once the tumor evolves to escape chemotherapy, there’s not much doctors today can do.
Reasons For Optimism
Still, specialists see two key reasons to expect the treatment picture to improve soon: immunotherapy and targeted treatments.
The idea of spurring the body’s own immune system holds great promise for tracking down and killing those cells doctors can’t see. It’s also flexible enough to adapt to changes in the cancer. Any true cure for glioblastoma will have to include manipulating the immune system, Curry said.
So far, though, immune therapies haven’t worked against glioblastoma. Drugs called checkpoint blockades have been very successful in a minority of patients with other tumor types, such as melanoma and some lung cancers. (Former President Jimmy Carter has been successfully treated with these drugs for melanoma that spread to his brain.) They work by lifting the brakes the cancer puts on the immune system. But glioblastoma seems to need some juice on the gas pedal, too, Golby said.
And triggering immune activity causes swelling. Think of what happens with a sprained ankle or broken toe. Swollen skin isn’t much of a problem, but swollen brain tissue has nowhere to go inside the skull, so it can wreak havoc on the patient, Loeffler said.
Some doctors are also optimistic about targeted therapies that exploit mutations in the genes of tumor cells to kill just the cancerous ones, leaving the healthy ones behind. A targeted therapy is unlikely to solve the problem, but a combination aimed at several genetic vulnerabilities might.
The explosion of genetic information available over the last few years has enabled a much deeper understanding of glioblastoma and where its weaknesses might lie, Loeffler said. “The more we know the more likely we are to be able to do something,” he said.
Ultimately, the solution will probably lie with a combination of approaches, said Dr. David Reardon, clinical director for the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, who was part of Ted Kennedy’s treatment team.
“I think my my sense is that we probably will at best likely achieve some modest benefit with these initial efforts,” he said. “Where we're really going to have to focus is to be able to bring these treatments into effective combinations. Unfortunately, this being such an aggressive and such a complex cancer, a single type of treatment is unlikely to be a home run.”
Crossing The Blood-Brain Barrier
One of the key challenges in treating glioblastoma is getting drugs across the so-called blood-brain barrier. Intended to protect the brain against invading viruses and bacteria, this barrier also keeps drugs from traveling through the bloodstream into the brain.
Paula Hammond, head of the department of chemical engineering at the Massachusetts Institute of Technology in Cambridge, has been working on ways to “hijack” the body’s own systems to get drugs across this barrier. By disguising her tiny, drug-carrying nanoparticles as proteins that normally carry iron across the barrier, she's been able to sneak them past the armor that lines the brain’s blood vessels, she said.
Then, she has to get those particles inside the tumor cells, which is the challenge she’s tackling now, said Hammond, of MIT’s Koch Institute of Integrative Cancer Research. “We believe we have a handle on a good stealth mechanism. Now, we’re looking at enhanced uptake,” she said. “We have to begin to think a little bit about how to get nature on our side on this one.”
At the Brigham, researchers are trying another approach to getting across the blood-brain-barrier: prying open holes in its armor with beams of ultrasound. Although normally used to take cool pictures during pregnancy, multiple beams of ultrasound aimed at the same area can make blood vessels of the brain “leakier,” according to research at the Brigham.
So far, most of the work remains in animals, but doctors in Toronto recently had success with the approach in people, so researchers are upbeat about this approach, Golby said.
There’s also a possibility that stem cells may be useful for tracking down and killing tumor cells. Khalid Shah, director for the Center for Stem Cell Therapeutics and Imaging at Brigham and Women’s Hospital, has been experimenting with delivering engineered stem cells directly to tumor sites after surgery.
Though the work is still in animals, he’s shown that these powerful stem cells can be taught to target only the rapidly dividing tumor cells, leaving the healthy tissue intact. By delivering the cells during surgery, Shah said, he gets around the problem of crossing the blood brain barrier. And his engineered cells seem to be able to travel out into the tendrils, away from the initial tumor site, he said.
He is currently awaiting federal approval to take his experiments into people, he said.
The bottom line, said William Curry at Mass. General, is that the longer a patient with glioblastoma can hang on, the better their chances of getting one of these new treatments.
“The longer you stay alive and the longer you maintain good neurological function, the more eligible you one may be to see the benefits and the fruits of a lot of the research that is really accelerating right now,” he said.
This segment aired on July 20, 2017.
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