When the brain goes bad, modern medicine is often powerless to help. That’s the case for Alzheimer’s disease, where drug after drug has failed, and the only approved treatments are marginally helpful at best. The same seems increasingly clear for the most common and aggressive type of brain cancer, glioblastoma multiforme. Its origins are mysterious, its ravages swift.
Fame and fortune can’t help those stricken. Glioblastoma multiforme, or GBM as it is known, killed US Senator Ted Kennedy in 2009, then ended the life of Senator John McCain exactly nine years later, despite them having arguably the world’s best healthcare. Benjamin Ivy, who ran an investment advisory firm, died from glioblastoma in 2005 at the age of 69. But after watching Ivy succumb, his wife Catherine (pictured) is trying to make fortune count, channeling their wealth into a foundation dedicated to GBM research.
Lately, she’s been running out of patience. “I’ve been doing this for 13 years and invested $90 million,” she told Xconomy at a recent meeting in San Francisco. “There’s been nothing.”
Death from brain and nervous system cancer is relatively rare, making up about 3 percent of US cancer deaths. GBM accounts for about 15 percent of all malignant brain tumors. Median survival is little more than a year, and the five-year survival rate is in the single digits, about 5 percent. Other than surgery and radiation, a few drugs—steroids, the chemotherapy temozolomide (Temodar), and bevacizumab (Avastin)—might give patients a few extra months.
Ben Ivy’s case was particularly cruel. Out on a hike with Catherine, his first symptoms were numbness in the thumb and an odd feeling in his tongue. Six weeks after surgery to remove his tumor, he began “walking a bit wobbly and struggling with his balance,’’ as Catherine Ivy described it. That was on a Friday. By the following Monday, he was paralyzed.
“He could not walk, eat, talk, or write,” Catherine Ivy said. Ben Ivy died four months after his initial diagnosis.
“Time is our most precious commodity,” Catherine Ivy said, which is why her biggest bet to date—$25 million initially, another $25 million in the wings—is on a single medical team with a cutting-edge idea, which, if it works, would speed the search for new drugs for patients who run out of time faster than any other people with cancer.
A Series of Disappointments
Recent failures to make a dent in GBM include checkpoint inhibitors, one of pharma’s most successful types of treatment in other forms of cancer.
The Bristol-Myers Squibb (NYSE: [[ticker:BMY]]) immunotherapy nivolumab (Opdivo), approved for nine types of cancer in less than five years, has failed twice in GBM trials. Another big test of Opdivo is due to report later this year.
Other Phase 3 failures include drugs from AbbVie and Celldex.
Progress is elusive for many reasons. First, the brain is a difficult organ to study in living humans, and a lab dish is a weak approximation—more so than other cancers. “We get fooled working in the lab with brain tumors,” says Nicholas Vitanza, who treats kids and young adults with brain tumors at Seattle Children’s Hospital. “Cells grow infinitely different they would in a patient. In the brain there are multiple cell populations.”
It’s also harder to try drugs out on brain cancer. GBM grows fast inside a confined space—the skull— pushing against the brain. Attacking it can exacerbate the inflammation and other side effects, including profound behavioral changes, that the tumor is already causing. At MD Anderson Cancer Center in Houston, patients aren’t allowed to join a clinical trial if there’s a danger of “midline shift”—the brain being pushed to one side—says Amy Heimberger, a neurosurgeon who studies the interplay of brain tumors and the immune system.
GBM changes fast, too, dodging and adapting to attacks like a shape-shifting villain in a superhero movie. Early 20th century attempts to stop GBM by cutting out the side of the brain where it was growing—a hemispherectomy—were thwarted when the cancer came back on the other side.
“No tumor type is as migratory or mutational as GBM,” says Nader Sanai, a neurosurgical oncologist the Barrow Neurological Institute.
Sanai is the beneficiary of Catherine Ivy’s impatience, as well as her current largesse. On the top floor of the Barrow, tucked into a dense medical center north of downtown Phoenix, Sanai is also director of the Ivy Brain Tumor Center, which the Ben & Catherine Ivy Foundation founded in 2018 with an initial $25 million to accelerate drug development.
The centerpiece of the program is what Sanai (pictured) calls “Phase 0” studies. The idea is to give a tiny, subtherapeutic dose of a drug just before surgery to remove a tumor. Once removed, the tumor tissue is analyzed to see if the drug penetrated the blood-brain barrier, moved into the tumor, and triggered any changes. If there’s significant drug activity, the patient is moved ahead to a more traditional study—this time, with a therapeutic dose.
The program is for GBM patients who have already undergone surgery, but whose tumor has grown back.
The big trick for Sanai’s team is to find the drugs that might clear all those hurdles. Here’s how that works: Sanai and his colleagues comb through medical literature to find drugs already tested or approved in other diseases, and which seem promising for GBM and other brain tumors. When they feel confident that a drug or combination of drugs could be helpful, they start a trial and look for patients. Only one such trial has been publicized so far. The Novartis (NYSE: [[ticker:NVS]]) drug ribociclib (Kisqali), approved to treat metastatic breast cancer, seemed a good fit because it blocks tumor proteins, known as CDK4 and CDK6, that GBM cells also use to multiply.
By the end of this year, the Ivy Center group expects to have 10 programs running on various drugs, according to Sanai. He declined to disclose other drugs in use without the owners’ permission.
To match patients to a Phase 0 study, Sanai’s team analyzes their original tumors, which were surgically removed after the original diagnosis. (The Barrow Neurological Institute has plenty of patients to consider, with more than 1,200 brain tumor surgeries a year.)
If a patient looks like a match, he or she is scheduled for another surgery, this time to remove the tumor that has returned. But twenty-four hours before the operation, the patient receives the subtherapeutic drug dose. After the surgery, Sanai’s team examines the fresh excised
