As her father fought his losing battle with glioblastoma, Meghan McCain asked her Twitter followers and “The View” audience last year to support two nonprofits that fund research on this notoriously aggressive and wily brain cancer.
The plea made experts wish, if only the main problem were money.
Sen. John McCain died Saturday at his home in Arizona. He was 81 and had been diagnosed with glioblastoma in July 2017. The son and grandson of Navy admirals, he became a Navy pilot and spent more than five years as a prisoner of war in Vietnam. A member of the U.S. Senate since 1987, McCain was the Republican candidate for president in 2008. Last year, two months after announcing that he had been diagnosed with cancer, he cast a pivotal vote against repealing the Affordable Care Act.
McCain faced grim odds.
About 14,000 people in the U.S. are diagnosed with glioblastoma, the most common form of adult brain cancer, every year. It will kill all but 15 percent within five years. Barely half live 18 months. Of two dozen experimental drugs tested in clinical trials for newly diagnosed glioblastoma in the last decade, zero improved survival. The last drug to do so, by an average of about two months, was temozolomide, approved in 2005. The newest treatment, based on electrical fields, bought patients an average of five more months.
“Glioblastoma is one of the most complex, drug-resistant, and adaptive cancers there is,” said David Arons, CEO of the National Brain Tumor Society, one of the groups Meghan McCain asked people to support. “There is no early detection and no prevention. Research is our only hope.”
On Saturday the society said in a statement, “If there is to be any upshot from this difficult news, it should be greater urgency with which this country rallies to support the nearly 700,000 Americans currently living with a glioblastoma or other brain tumor, while honoring the brave that have been taken from us by this disease.”
While there is no disagreement that research is the answer, experts are deeply divided about what direction the research should take. “The lack of truly innovative thinking around [glioblastoma] has been a thorn in my side for some time,” said Anna Barker, of Arizona State University, who as deputy director of the National Cancer Institute led The Cancer Genome Atlas (TCGA), the 10-year, $375 million mega-project to discover all the mutations in 33 different cancers in hopes of finding their Achilles’ heels. Instead of out-of-the-box thinking, she said, most research on glioblastoma focuses “on genes we know, pathways we think we know, and drugs that have worked in other cancers. What’s out there and what’s on the [research] agenda is very underwhelming.”
Which is not to say that glioblastoma researchers don’t have proposals for how they’d spend a windfall. A few even have ideas for novel approaches, which they lament are in limbo for lack of funding. The deep divide is over what constitutes an “innovative” idea and whether that’s where effective, new treatments will come from, as Barker contends, or whether something short of that could bring meaningful advances.
There is no disagreement about the challenge.
“Glioblastoma is one of the most complex, drug-resistant, and adaptive cancers there is.”
David Arons, National Brain Tumor Society
The velociraptor problem
By “drug resistant” and “adaptive,” Arons is referring to how glioblastoma responds to surgery, radiation, and then temozolomide, the standard protocol: It usually shrinks initially, or even becomes too small to detect, but eventually comes roaring back. “It reacts to treatment like a velociraptor,” Arons said, turning more and more aggressive the more it’s attacked.
Understanding those changes, which go by the innocent-sounding name “tumor evolution,” requires analyzing the tumor before surgery, after surgery, after radiation, and after temozolomide, Arons said: “What’s happening at the molecular and cellular level? What proteins are being expressed more? How is it evolving into a monster?”
The brain tumor society is partly funding one major effort to answer those questions. Called the GLASS Consortium, it aims to track tumor evolution by sequencing the genomes of glioblastoma cells (obtained during surgery or through subsequent biopsy) at multiple time points “to understand why the tumor changes and stops responding to therapy,” said computational biologist Roel Verhaak, of the Jackson Laboratory, who is part of the GLASS group. “But we don’t have the funding to do the 500 patients we need,” which he estimates would cost $10 million.
A single glioblastoma contains cells with many different mutations, a big reason why the cancer almost always recurs after the first round of surgery, radiation, and chemo. “There is a residual population of tumor-initiating cells that the initial treatment didn’t kill, which can regrow the tumor,” said neuro-oncologist Dr. Shiao-Pei Weathers of MD Anderson Cancer Center. “And blocking a single pathway isn’t going to make much difference to patient outcomes: These tumors are too heterogeneous,” so even if the therapy blocks one tumor-fueling pathway the cancer detours to an alternative route.
“I bet we’ll need 20 different drugs to treat this thing. ”
Dr. Madan Kwatra, Duke University
That suggests that only multiple simultaneous therapies will have a chance against glioblastoma. “I bet we’ll need 20 different drugs to treat this thing,” said Dr. Madan Kwatra of Duke University.
Everyone hopes that’s hyperbole, but there’s wide agreement that combination therapy will be needed. For instance, genetically engineered immune cells called CAR-Ts have extended survival in some forms of leukemia, but will likely fail in glioblastoma: They may kill a large fraction of tumor cells (those that display the molecule that the T cells are programmed to attack, as scientists reported earlier this year), but survivors (those not displaying the molecule) will re-grow and spread.
“The heterogeneity of resistance is a huge problem, and that’s why we need to study combinations, since right now we don’t understand the combinations that might help,” said Dr. Patrick Wen of Dana-Farber Cancer Institute, president of the Society for Neuro-Oncology.
Combination research generally falls in the cracks: too boring for NCI to fund but too speculative for drug companies. “We have all these good ideas for rational combinations,” Weathers said. “But at the end of the day you can’t run a clinical trial without money.” She would like to test a one-two punch of drugs from two companies, and though each is willing to provide supplies of drug, neither will fund the actual study. “They say glioblastoma just isn’t a priority for them,” she said.
Private money could help plug the funding gap, enabling scientists to do small clinical trials and, hopefully, find something that looks promising enough for drug companies to pick up for larger trials. “Many drugs out there might be useful for brain cancer but aren’t thought of for it,” said Wen. “Most drug companies don’t care about brain cancer, so we’ve had to do our own Phase 1 trials. That’s where we need more funding.”
The kitchen sink
Arons believes in throwing everything in biologists’ bag of tricks at glioblastoma: grow brain organoids to quickly screen experimental drugs, for instance, and transplant bits of glioblastoma from as many patients as possible into mice and douse them with drug after drug after drug to find one that helps.
“We want to change the mindset that glioblastoma is where cancer drugs go to die.”
Anna Barker, Arizona State University
That brute force approach reflects a hunch that drugs in development or already approved for other cancers might work against glioblastoma, too. For instance, TCGA found that several genes that are often mutated in glioblastoma are also mutated in other cancers: ERBB2 in breast cancer, and TP53 and PIK3R1 in several.
Whether one drug or several, they obviously have to reach the brain, but many cancer drugs — Wen estimates 90 percent — can’t cross the blood-brain barrier.
If scientists can figure out the way in, “it might be possible to repurpose drugs that appeared to have some level of efficacy against glioblastoma but which were [hampered] by not being able to penetrate the blood-brain barrier,” said Dr. Nicholas Butowski, a brain tumor surgeon at the University of California, San Francisco.
An international study led by a nonprofit at ASU, called GBM Agile, will test both single therapies and combinations, approved and experimental. Duds will be immediately dropped from the trial. If any seem effective, data on the patients who benefitted (including their tumors’ genetics and other molecular markers) will be sent to the manufacturer so it can conduct a late-stage clinical trial with the aim of testing it in only that kind of patient.
GBM Agile, which depends on philanthropic donations and hopes to get underway this year, is currently negotiating with manufacturers to donate drugs for testing. “We want to change the mindset that glioblastoma is where cancer drugs go to die,” Barker said.
Although the average survival benefit with temozolomide is a couple of months, it increased the percentage of patients who survive five years from about 2 percent to 8 percent. “There are a few patients who benefit a lot,” said neuro-oncologist Dr. Michael Salacz of the University of Kansas, “but we don’t know what it is about their glioblastoma that explains that.” Identifying genetic or other biomarkers that predict who will be a lucky outlier, he said, could make a meaningful difference to patients.
The immuno- approach
Coaxing the immune system to attack cancer cells has transformed the treatment of, and prognosis for, types of cancer that had previously been nearly as intractable as glioblastoma. Because many patients don’t respond to the new immuno-oncology drugs, researchers are scrambling to do better, including by creating vaccines that prime the immune system to attack molecules on cancer cells. At the recent annual meeting of the American Society of Clinical Oncology, researchers reported that in a Phase 2, single-arm trial 91 percent of the newly-diagnosed patient receiving the SurVaxM vaccine, plus standard therapy, were still alive after a year. That compares to the usual 61 percent of those on standard therapy alone. It’s too soon to know if glioblastoma eventually defeats the immune system as it does everything else.
Correction: This story has been corrected to say that a new therapy uses electrical fields, not electromagnetic waves.