An aggressive brain tumor comes into molecular focus

Yair Gozal, MD, PhD, speaks about glioblastoma at Mayfield’s annual meeting.

Fifty years ago the median survival for an individual diagnosed with glioblastoma multiforme, the aggressive brain cancer, was 7 months. Today it is 15 months.

“Survival has doubled, but it’s still not very long,” said Yair Gozal, MD, PhD, a neurosurgeon and brain tumor specialist at Mayfield Brain & Spine. “Even someone like Senator John McCain, who had every resource at his disposal – the best doctors, the best surgeons, every medicine available – survived only 13 months.

“We’ve invested millions and millions of dollars trying to cure cancer, glioblastoma. We’ve done a good job with breast cancer and testicular cancer, but we’ve made little headway with glioblastoma. Why is that?”

In a lecture to associates, managers, and physicians at Mayfield’s annual meeting, Dr. Gozal explored the frustrations of this lethal brain tumor, its mysteries, current standard treatments, and the promise of future therapies. Although Dr. Gozal and his colleagues have only three major treatment protocols to work with — surgical removal of as much tumor as possible, followed by radiation and one type of chemotherapy (Temodar) – for the first time they know what the tools of tomorrow will look like. The next generation of therapies will appear as vaccines and molecular agents that target specific aspects of the various subtypes of glioblastoma, also known as GBM.

“We know now that it’s not just one disease,” Dr. Gozal said. “It’s many diseases. The future is targeted drug development, a personalized approach to the type of tumor that a person has.”

You can support brain tumor research through Peter Carr’s
Bike for GBM fund at the Mayfield Education & Research Foundation >

Glioblastoma strikes 17,000 Americans a year, affects 135,000 at any given time, and exacts a six-month cost of care of nearly $140,000 per patient. It accounts for 80 percent of all malignant tumors that originate in the brain. It has traditionally been labeled a grade 4 among glioma tumors, which originate from the glial cells, with grading determined by how virulent the tumor’s cells appear under a microscope.

Beginning in 2006 the Cancer Genome Atlas, whose co-investigators included Mayfield’s Christopher McPherson, MD, began mapping the genome of grade 4 gliomas (glioblastoma) and later grade 3 gliomas. The researchers began seeing brain cancer in a new way, with subtypes characterized by biomarkers that anticipate a likely disease process, predict how a patient will respond to a particular treatment, and even foretell a patient’s likely survival.

“There are thousands of biomarkers out there for GBM,” Dr. Gozal said. “But there are currently four that we use every day in practice.” Those four are:

  • A mutated form of MGMT, a protein that repairs errors in DNA. In its mutated form, MGMT’s repair work is compromised. As a result, tumor cells whose DNA is damaged by chemotherapy are less likely to survive. So patients with this mutation do better, with a 2-year survival rate of 46 percent.
  • A missing section on two chromosomes, called the 1p/19q codeletion. This biomarker indicates a less malign form of cancer, known as oligodendroglioma. Relatively speaking, it is a positive sign for patients, whose median survival is 7 years. Patients whose 1p/19q is intact have a median survival of 2.8 years.
  • IDH1 and IDH2 mutations, which cause tumor cells to grow and divide. Patients who have these mutations live longer on average than those who do not.
  • EGFR (epidermal growth factor receptor) mutation, in which a little switch on the tumor is permanently turned on. As such, the switch is a target for a vaccine-like drug, rindopeptimut, which emerged as the first targeted therapy for glioblastoma.

“In the first trial, patients with the EGFR mutation who were given the rindopeptimut therapy survived 22 months compared to 16 months for those who did not,” Dr. Gozal said. “But a more recent trial was not as successful. We’re following along and will see whether this will bear out for people with this one receptor.”

Scientists are also sub-dividing glioblastoma into four subclasses based on their total molecular makeup. “When we look at individual proteins or genes, we’re not seeing the entire picture,” Dr. Gozal said. “We’re seeing one thing. And those genes and proteins interact with many other genes and proteins and tell a different story. And so now scientists are taking a 10,000-foot view to figure out how these genes are interacting, and what gets altered, and why this disease progresses so quickly.”

The four classes of glioblastoma are classical, mesenchymal, proneural, and neural. All have genes that have mutated, and all have different survival profiles. As yet, there is no available therapy that targets any of these sub-types.

In addition to the three primary glioblastoma treatments currently available – surgery, radiosurgery and chemotherapy – physicians have two secondary treatments that may prolong life a few months: 1) the drug Avastin, which prevents new tumor-feeding blood vessels from developing; and 2) tumor treating field (TTF) therapy, which involves wearing a device resembling a bathing cap that delivers electromagnetic energy to the scalp. Both treatments have drawbacks. Avastin produces serious side effects; TTF therapy requires patients to shave their heads daily and wear the device for 18 hours a day over a period of weeks.

Jenny’s story: a tumor, a dragon slayer, and the gift of time >

One ray of hope has appeared recently, right here in Greater Cincinnati. It involves Bob Rulli, a patient of Mayfield’s Brad Skidmore, MD, whose story was written up in the Cincinnati Enquirer. Mr. Rulli, initially diagnosed in 2013, had already survived three years when his glioblastoma tumor reappeared in 2016. At that point he enrolled in a Phase 1 clinical trial of BXQ-350, an experimental drug discovered in 2002 by a Cincinnati scientist, Xiaoyang Qi, PhD, and now manufactured by Bexion Pharmaceuticals in Covington, Kentucky.

It is too soon to say whether BXQ-350 will be affective for a subset of patients with glioblastoma. Bexion has reported partial results from its Phase 1 study, and a Phase II trial is being planned. Certainly there is one very happy family.

“Bob Rulli was treated over a period of 19 months,” Dr. Gozal said. “And now, five years after his diagnosis, he’s still alive.”

— Cindy Starr